3561 lines
306 KiB
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3561 lines
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Entry
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- *611295 - KELCH-LIKE 24; KLHL24
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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">*611295</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/611295">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div 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=ENSG00000114796;t=ENST00000242810" 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=54800" 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=611295" 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=ENSG00000114796;t=ENST00000242810" 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_001349413,NM_001349414,NM_001349415,NM_001349416,NM_001349417,NM_001349418,NM_001349419,NM_001349420,NM_001349421,NM_001349422,NM_001349423,NM_001349424,NM_001349425,NM_001349426,NM_001349428,NM_001349429,NM_017644,NR_146169,NR_146170,XM_005247552,XM_017006653,XM_017006655,XM_017006658,XM_047448371,XM_047448372,XM_047448373,XM_047448374,XM_047448375" 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_017644" 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=611295" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=16838&isoform_id=16838_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/KLHL24" 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/7019911,10439155,38196038,40018614,51981708,57997570,57997586,74722812,115383343,119598725,119598726,148745763,530374820,1034634009,1034634013,1034634019,1159261108,1159261116,1159261120,1159261126,1159261130,1159261134,1159261147,1159261157,1159261159,1159261161,1159261171,1159261192,1159261196,1159261212,1159261226,1159261236,2217344543,2217344549,2217344551,2217344553,2217344555,2462590710,2462590712,2462590714,2462590716,2462590718,2462590720,2462590722,2462590724,2462590726" 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/Q6TFL4" 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=54800" 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=ENSG00000114796;t=ENST00000242810" 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=KLHL24" 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=KLHL24" 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+54800" 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/KLHL24" 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:54800" 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/54800" 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=chr3&hgg_gene=ENST00000242810.11&hgg_start=183635623&hgg_end=183684519&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:25947" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=611295[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=611295[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000114796" 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=KLHL24" 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=KLHL24" 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=KLHL24" 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=KLHL24&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/PA142671576" 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:25947" 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:1923035" 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/KLHL24#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:1923035" 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/54800/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=54800" 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-040426-1185" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=KLHL24&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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611295
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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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KELCH-LIKE 24; KLHL24
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</span>
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</h3>
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</div>
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<div>
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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KAINATE RECEPTOR-INTERACTING PROTEIN FOR GLUR6; KRIP6
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=KLHL24" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">KLHL24</a></em></strong>
|
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/3/900?start=-3&limit=10&highlight=900">3q27.1</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:183635623-183684519&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'})">3:183,635,623-183,684,519</a> </span>
|
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</em>
|
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</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>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
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Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=620236,617294" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
|
|
|
<tr>
|
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<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/3/900?start=-3&limit=10&highlight=900">
|
|
3q27.1
|
|
</a>
|
|
</span>
|
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</td>
|
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|
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<td>
|
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<span class="mim-font">
|
|
Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/620236"> 620236 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
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</span>
|
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</td>
|
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<td>
|
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<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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|
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/617294"> 617294 </a>
|
|
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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|
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</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>
|
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</table>
|
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</div>
|
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/611295" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/611295" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
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<p>KLHL24 is a member of the Kelch-like protein family, which act as substrate-specific adaptors to cullin (see <a href="/entry/603134">603134</a>) E3 ubiquitin ligases and which are involved in a variety of cellular processes such as cytoskeletal organization, regulation of cell morphology, cell migration, protein degradation, and gene expression (summary by <a href="#4" class="mim-tip-reference" title="Hedberg-Oldfors, C., Abramsson, A., Osborn, D. P. S., Danielsson, O., Fazlinezhad, A., Nilipour, Y., Hubbert, L., Nennesmo, I., Visuttijai, K., Bharj, J., Petropoulou, E., Shoreim, A., and 12 others. <strong>Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24.</strong> Hum. Molec. Genet. 28: 1919-1929, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30715372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30715372</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30715372[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddz032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30715372">Hedberg-Oldfors et al., 2019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30715372" 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="Laezza, F., Wilding, T. J., Sequeira, S., Coussen, F., Zhang, X. Z., Hill-Robinson, R., Mulle, C., Huettner, J. E., Craig, A. M. <strong>KRIP6: a novel BTB/kelch protein regulating function of kainate receptors.</strong> Molec. Cell. Neurosci. 34: 539-550, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17254796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17254796</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17254796[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.mcn.2006.12.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17254796">Laezza et al. (2007)</a> used the C-terminal domain of GluR6 (<a href="/entry/138244">138244</a>), a kainate receptor found at synapses in the central nervous system, as bait in a yeast 2-hybrid screen of a rat forebrain cDNA library and identified a novel protein, KLHL24, which they called KRIP6. KLHL24 contains a BTB/POZ domain near the N-terminus followed by a BACK domain and 6 consecutive kelch repeats. The BTB/POZ domain is a zinc finger and protein-protein dimerization domain. The BACK domain is similar to substrate-specific adaptors for protein ubiquitination, and the 6 kelch repeats likely form a beta-propeller structure. In situ hybridization and immunohistochemistry experiments showed that KLHL24 is widely expressed in rat brain, particularly in the cortex and hippocampus where expression of GluR6 is also prominent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17254796" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By RT-PCR, <a href="#6" class="mim-tip-reference" title="Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others. <strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong> Nature Genet. 48: 1508-1516, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>] [<a href="https://doi.org/10.1038/ng.3701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27798626">Lin et al. (2016)</a> detected ubiquitous expression of human KLHL24 in representative adult tissues, including skin. Immunoprecipitation analysis of mouse skin and cerebral tissue was consistent with previous reports that Klhl24 is expressed at higher levels in the cerebral cortex than in skin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27798626" 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="#3" class="mim-tip-reference" title="He, Y., Maier, K., Leppert, J., Hausser, I., Schwieger-Briel, A., Weibel, L., Theiler, M., Kiritsi, D., Busch, H., Boerries, M., Hannula-Jouppi, K., Heikkila, H., Tasanen, K., Castiglia, D., Zambruno, G., Has, C. <strong>Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.</strong> Am. J. Hum. Genet. 99: 1395-1404, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889062</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27889062[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.2016.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889062">He et al. (2016)</a> used RT-PCR in human skin and skin cells and found expression of KLHL24 in all main skin cell types, including keratinocytes, dermal fibroblasts, and melanocytes. By immunofluorescence staining, KLHL24 was detected intracellularly and at the cell periphery, where it partially colocalized with desmoplakin (DSP; <a href="/entry/125647">125647</a>) and E-cadherin (CDH1; <a href="/entry/192090">192090</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27889062" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Yenamandra, V. K., van den Akker, P. C., Lemmink, H. H., Jan, S. Z., Diercks, G. F. H., Vermeer, M., van den Berg, M. P., van der Meer, P., Pasmooij, A. M. G., Sinke, R. J., Jonkman, M. F., Bolling, M. C. <strong>Cardiomyopathy in patients with epidermolysis bullosa simplex with mutations in KLHL24.</strong> Brit. J. Derm. 179: 1181-1183, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29779254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29779254</a>] [<a href="https://doi.org/10.1111/bjd.16797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29779254">Yenamandra et al. (2018)</a> performed immunofluorescence antigen mapping on human embryonic stem cell-derived cardiomyocytes and observed clear positive staining of KLHL24 along the cell membrane. The authors noted that the distribution pattern was similar to that of other intercalated disc proteins involved in cardiocutaneous syndromes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29779254" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Scott, A. F. <strong>Personal Communication.</strong> Baltimore, Md. 7/31/2007."None>Scott (2007)</a> mapped the KLHL24 gene to chromosome 3q27.1 based on an alignment of the KLHL24 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AC068769" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AC068769</a>) with the genomic sequence (build 36.2).</p>
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<p><a href="#5" class="mim-tip-reference" title="Laezza, F., Wilding, T. J., Sequeira, S., Coussen, F., Zhang, X. Z., Hill-Robinson, R., Mulle, C., Huettner, J. E., Craig, A. M. <strong>KRIP6: a novel BTB/kelch protein regulating function of kainate receptors.</strong> Molec. Cell. Neurosci. 34: 539-550, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17254796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17254796</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17254796[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.mcn.2006.12.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17254796">Laezza et al. (2007)</a> confirmed interaction between KLHL24 and GluR6 in vivo through coexpression of epitope-tagged KLHL24 with GluR6 in COS-7 cells. The 2 proteins colocalized in a perinuclear pattern. Coimmunoprecipitation experiments also showed that the 2 proteins interact. Coexpression of KLHL24 and GluR6 changed currents observed in patch-clamp experiments, suggesting that binding of KLHL24 to GluR6 alters channel operation. Overexpression of KLHL24 reduced endogenous kainate receptor-mediated responses evoked in hippocampal neurons. <a href="#5" class="mim-tip-reference" title="Laezza, F., Wilding, T. J., Sequeira, S., Coussen, F., Zhang, X. Z., Hill-Robinson, R., Mulle, C., Huettner, J. E., Craig, A. M. <strong>KRIP6: a novel BTB/kelch protein regulating function of kainate receptors.</strong> Molec. Cell. Neurosci. 34: 539-550, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17254796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17254796</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17254796[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.mcn.2006.12.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17254796">Laezza et al. (2007)</a> speculated that high levels of KLHL24 might protect neurons during high frequency release of glutamate by inhibiting peak current mediated by kainate receptors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17254796" 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 mouse keratinocytes, <a href="#6" class="mim-tip-reference" title="Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others. <strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong> Nature Genet. 48: 1508-1516, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>] [<a href="https://doi.org/10.1038/ng.3701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27798626">Lin et al. (2016)</a> observed that mRNA levels of Klhl24 increased significantly during differentiation, to a degree similar to that of the keratinocyte differentiation markers Lor (<a href="/entry/152445">152445</a>) and Krt10 (<a href="/entry/148080">148080</a>). In addition, Krt14 (<a href="/entry/148066">148066</a>) protein levels significantly decreased upon differentiation, with slightly increased mRNA levels, suggesting protein degradation. Expression of increasing amounts of KLHL24 in HEK293T cells resulted in a concomitant dose-dependent decrease in KRT14 abundance, and knockdown of KLHL24 in HaCaT cells markedly increased KRT14 protein levels. FISH assay of human skin samples from both patients (see MOLECULAR GENETICS) and controls showed lower KLHL24 expression in basal-layer keratinocytes than suprabasal keratinocytes, a pattern opposite to that of KRT14 expression. <a href="#6" class="mim-tip-reference" title="Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others. <strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong> Nature Genet. 48: 1508-1516, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>] [<a href="https://doi.org/10.1038/ng.3701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27798626">Lin et al. (2016)</a> noted that the inverse correlation of KLHL24 mRNA levels and KRT14 protein levels in both human and mouse keratinocytes was consistent with a model in which KLHL24 functions as an E3 ligase for KRT14 ubiquitination and degradation, suggesting that KLHL24 has a role in the loss of KRT14 during keratinocyte differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27798626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Epidermolysis Bullosa Simplex 6, with Scarring and Hair Loss, with or without Dilated Cardiomyopathy</em></strong></p><p>
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In 5 unrelated patients with generalized epidermolysis bullosa simplex with scarring and hair loss (EBS6; <a href="/entry/617294">617294</a>), <a href="#6" class="mim-tip-reference" title="Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others. <strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong> Nature Genet. 48: 1508-1516, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>] [<a href="https://doi.org/10.1038/ng.3701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27798626">Lin et al. (2016)</a> identified heterozygosity for mutations in the start codon of the KLHL24 gene (<a href="#0001">611295.0001</a>-<a href="#0003">611295.0003</a>). Analysis of transfected HEK293T cells showed that all 3 mutations resulted in an N-terminally truncated protein lacking the first 28 amino acids, and that met29 serves as an alternative initiation site. Although patient mRNA levels were comparable to control, transfection studies in HaCaT cells showed markedly higher protein levels for the mutant compared to wildtype; further experiments indicated that autoubiquitination is abolished with the KLHL24 mutant, resulting in enhanced protein stability and higher abundance. After identifying KRT14 as a candidate ubiquitination substrate of KLHL24, the authors observed dramatically lower KRT14 levels in patient skin samples compared to controls and noted that KRT5 (<a href="/entry/148040">148040</a>) levels were also lower than in controls. <a href="#6" class="mim-tip-reference" title="Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others. <strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong> Nature Genet. 48: 1508-1516, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>] [<a href="https://doi.org/10.1038/ng.3701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27798626">Lin et al. (2016)</a> concluded that KLHL24 is an E3 ligase for KRT14 and that these gain-of-function variants induce excessive ubiquitination and degradation of KRT14, resulting in KRT14 loss and skin fragility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27798626" 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 10 unrelated families with generalized EBS, <a href="#3" class="mim-tip-reference" title="He, Y., Maier, K., Leppert, J., Hausser, I., Schwieger-Briel, A., Weibel, L., Theiler, M., Kiritsi, D., Busch, H., Boerries, M., Hannula-Jouppi, K., Heikkila, H., Tasanen, K., Castiglia, D., Zambruno, G., Has, C. <strong>Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.</strong> Am. J. Hum. Genet. 99: 1395-1404, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889062</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27889062[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.2016.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889062">He et al. (2016)</a> identified heterozygosity for mutations in the start codon of KLHL24; affected individuals from 9 of the families had the recurrent c.1A-G mutation (<a href="#0001">611295.0001</a>), and 1 patient had a c.2T-C transition (<a href="#0004">611295.0004</a>). RT-PCR of patient keratinocytes showed that the mutations did not result in reduced transcription or in mRNA decay; however, immunostaining showed a reduction of KLHL24 signal in the cytoplasm and at the cell periphery compared to control keratinocytes. In cultured patient keratinocytes, KRT14 staining appeared disorganized, irregular, and fragmented, whereas KRT5, tubulin, and actin were not significantly changed. In heat-stressed patient keratinocytes, KRT14 abnormalities were even more pronounced, with perinuclear distribution and fragmentation, suggesting increased depolymerization after stress induction, whereas control cells changed very little. In addition, the overall abundance of ubiquitinated proteins increased in control cells after heat stress, but did not change significantly in patient cells. Noting augmented phosphorylation of the stress-activated kinase p38 (see <a href="/entry/600289">600289</a>) and a 2-fold increase in apoptosis in mutant keratinocytes, <a href="#3" class="mim-tip-reference" title="He, Y., Maier, K., Leppert, J., Hausser, I., Schwieger-Briel, A., Weibel, L., Theiler, M., Kiritsi, D., Busch, H., Boerries, M., Hannula-Jouppi, K., Heikkila, H., Tasanen, K., Castiglia, D., Zambruno, G., Has, C. <strong>Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.</strong> Am. J. Hum. Genet. 99: 1395-1404, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889062</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27889062[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.2016.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889062">He et al. (2016)</a> suggested that ubiquitination and subsequent proteasomal degradation of KRT14 might be disturbed in the presence of KLHL24 mutations, resulting in cellular stress and apoptosis. Immunoblotting showed amounts of KRT5 and KRT14 that were 1.5- to 2-fold higher in cell lysates from mutant keratinocytes than from controls, and KRT15 (<a href="/entry/148030">148030</a>) was also strongly upregulated in patient skin and keratinocytes compared to controls. In contrast to the findings by <a href="#6" class="mim-tip-reference" title="Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others. <strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong> Nature Genet. 48: 1508-1516, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>] [<a href="https://doi.org/10.1038/ng.3701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27798626">Lin et al. (2016)</a>, <a href="#3" class="mim-tip-reference" title="He, Y., Maier, K., Leppert, J., Hausser, I., Schwieger-Briel, A., Weibel, L., Theiler, M., Kiritsi, D., Busch, H., Boerries, M., Hannula-Jouppi, K., Heikkila, H., Tasanen, K., Castiglia, D., Zambruno, G., Has, C. <strong>Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.</strong> Am. J. Hum. Genet. 99: 1395-1404, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889062</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27889062[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.2016.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889062">He et al. (2016)</a> observed that while recombinant overexpression of normal KLHL24 in HaCaT keratinocytes promoted KRT14 degradation, mutant KLHL24 showed less activity than the wildtype molecule. The latter authors concluded that KLHL24 mutations cause skin fragility, and that KLHL24 plays a role in maintaining the balance between intermediate filament stability and degradation required for skin integrity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27798626+27889062" 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 Dutch family in which a father and son had EBS, with the father also showing dilated cardiomyopathy (CMD) and the 14-year-old son showing a borderline enlarged left ventricle, <a href="#11" class="mim-tip-reference" title="Yenamandra, V. K., van den Akker, P. C., Lemmink, H. H., Jan, S. Z., Diercks, G. F. H., Vermeer, M., van den Berg, M. P., van der Meer, P., Pasmooij, A. M. G., Sinke, R. J., Jonkman, M. F., Bolling, M. C. <strong>Cardiomyopathy in patients with epidermolysis bullosa simplex with mutations in KLHL24.</strong> Brit. J. Derm. 179: 1181-1183, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29779254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29779254</a>] [<a href="https://doi.org/10.1111/bjd.16797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29779254">Yenamandra et al. (2018)</a> identified heterozygosity for the recurrent c.1A-G mutation in the KLHL24 gene. In experiments using 3D cardiac tissue engineered from pluripotent stem cells derived from the Dutch father and son, <a href="#10" class="mim-tip-reference" title="Vermeer, M. C. S. C., Bolling, M. C., Bliley, J. M., Arevalo Gomez, K. F., Pavez-Giani, M. G., Kramer, D., Romero-Herrera, P. H., Westenbrink, B. D., Diercks, G. F. H., van den Berg, M. P., Feinberg, A. W., Sillje, H. H. W., van der Meer, P. <strong>Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues.</strong> J. Clin. Invest. 131: e140615, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34292882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34292882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34292882[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/10.1172/JCI140615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34292882">Vermeer et al. (2021)</a> demonstrated that the presence of the gain-of-function KLHL24 mutation in cardiomyocytes results in excessive degradation of desmin (DES; <a href="/entry/125660">125660</a>), affecting tissue morphology and function, which could be prevented by restoring desmin protein levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=29779254+34292882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Schwieger-Briel, A., Fuentes, I., Castiglia, D., Barbato, A., Greutmann, M., Leppert, J., Duchatelet, S., Hovnanian, A., Burattini, S., Yubero, M. J., Ibanez-Arenas, R., Rebolledo-Jaramillo, B., and 9 others. <strong>Epidermolysis bullosa simplex with KLHL24 mutations is associated with dilated cardiomyopathy.</strong> J. Invest. Derm. 139: 244-249, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30120936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30120936</a>] [<a href="https://doi.org/10.1016/j.jid.2018.07.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30120936">Schwieger-Briel et al. (2019)</a> restudied 10 patients with EBS6 and the c.1A-G mutation from 6 families that were previously reported by <a href="#3" class="mim-tip-reference" title="He, Y., Maier, K., Leppert, J., Hausser, I., Schwieger-Briel, A., Weibel, L., Theiler, M., Kiritsi, D., Busch, H., Boerries, M., Hannula-Jouppi, K., Heikkila, H., Tasanen, K., Castiglia, D., Zambruno, G., Has, C. <strong>Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.</strong> Am. J. Hum. Genet. 99: 1395-1404, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889062</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27889062[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.2016.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889062">He et al. (2016)</a>, and found that the patients exhibited evidence of cardiac involvement with either elevated cardiac biomarkers or documented CMD. <a href="#8" class="mim-tip-reference" title="Schwieger-Briel, A., Fuentes, I., Castiglia, D., Barbato, A., Greutmann, M., Leppert, J., Duchatelet, S., Hovnanian, A., Burattini, S., Yubero, M. J., Ibanez-Arenas, R., Rebolledo-Jaramillo, B., and 9 others. <strong>Epidermolysis bullosa simplex with KLHL24 mutations is associated with dilated cardiomyopathy.</strong> J. Invest. Derm. 139: 244-249, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30120936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30120936</a>] [<a href="https://doi.org/10.1016/j.jid.2018.07.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30120936">Schwieger-Briel et al. (2019)</a> also identified 2 more EBS probands with the KLHL24 c.1A-G mutation; both women had normal echocardiograms at ages 35 and 28, although 1 proband reported a syncopal episode. In addition, the authors studied a Chilean family in which 8 members had EBS and were heterozygous for a different mutation in the translation initiation codon of KLHL24 (c.2T-G; <a href="#0007">611295.0007</a>); all 6 living members had elevated cardiac biomarkers, and 3 had documented CMD, and 2 family members had died a 'cardiac death' with CMD by history. Whole-exome sequencing and multigene panel data showed no pathogenic variants in known CMD-associated genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30120936+27889062" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="El Hachem, M., Barresi, S., Diociaiuti, A., Boldrini, R., Condorelli, A. G., Capoluongo, E., Proto, V., Scuvera, G., Has, C., Tartaglia, M., Castiglia, D. <strong>Phenotypic features of epidermolysis bullosa simplex due to KLHL24 mutations in 3 Italian cases.</strong> Acta Derm. Venereol. 99: 238-239, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30226531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30226531</a>] [<a href="https://doi.org/10.2340/00015555-3046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30226531">El Hachem et al. (2019)</a> reported 3 children with EBS and heterozygosity for de novo mutations in the start codon of the KLHL24 gene: 2 boys, a 7-year-old and an infant, were heterozygous for the c.2T-C variant (<a href="#0004">611295.0004</a>), and a 5-year-old girl was heterozygous for the c.3G-A variant (<a href="#0003">611295.0003</a>). Cardiac evaluation, including screening for cardiomyopathy markers, was normal in all 3 of the children, although the authors noted that due to the young ages of the patients, possible future cardiac complications could not be excluded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30226531" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 14-year-old girl with EBS and severe CMD requiring heart transplantation, <a href="#2" class="mim-tip-reference" title="Grilletta, E. A. <strong>Cardiac transplant for epidermolysis bullosa simplex with KLHL24 mutation-associated cardiomyopathy.</strong> JAAD Case Rep. 5: 912-914, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31649980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31649980</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31649980[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.jdcr.2019.08.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31649980">Grilletta (2019)</a> analyzed a panel of EB-associated genes and identified heterozygosity for a mutation in the initiation codon of KLHL24 (c.1A-T; <a href="#0008">611295.0008</a>). Because she was adopted, familial segregation could not be ascertained. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31649980" 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>Familial Hypertrophic Cardiomyopathy 29 with Polyglucosan Bodies</em></strong></p><p>
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In 2 unrelated families segregating autosomal recessive hypertrophic cardiomyopathy (CMH29; <a href="/entry/620236">620236</a>), <a href="#4" class="mim-tip-reference" title="Hedberg-Oldfors, C., Abramsson, A., Osborn, D. P. S., Danielsson, O., Fazlinezhad, A., Nilipour, Y., Hubbert, L., Nennesmo, I., Visuttijai, K., Bharj, J., Petropoulou, E., Shoreim, A., and 12 others. <strong>Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24.</strong> Hum. Molec. Genet. 28: 1919-1929, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30715372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30715372</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30715372[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddz032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30715372">Hedberg-Oldfors et al. (2019)</a> identified homozygosity for mutations in the KLHL24 gene: in family A, of Iraqi origin, an affected brother and sister were homozygous for a nonsense mutation (E350X; <a href="#0005">611295.0005</a>); and in family B, of Iranian origin, 4 sibs and an affected cousin were homozygous for a missense mutation (R306H; <a href="#0006">611295.0006</a>). The unaffected parents in both pedigrees were heterozygous for the respective mutations, neither of which was found in the Greater Middle Eastern Variome database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30715372" 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="#6" class="mim-tip-reference" title="Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others. <strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong> Nature Genet. 48: 1508-1516, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>] [<a href="https://doi.org/10.1038/ng.3701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27798626">Lin et al. (2016)</a> generated knockin mice with the KLHL24 c.3G-T mutation (<a href="#0002">611295.0002</a>) and observed lower body weight, smaller body size, and more pronounced age-related hair loss than their wildtype littermates. Klhl24-null mice appeared grossly normal, and neither Klhl24-null mice or those carrying the c.3G-T variant showed signs of skin fragility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27798626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Hedberg-Oldfors, C., Abramsson, A., Osborn, D. P. S., Danielsson, O., Fazlinezhad, A., Nilipour, Y., Hubbert, L., Nennesmo, I., Visuttijai, K., Bharj, J., Petropoulou, E., Shoreim, A., and 12 others. <strong>Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24.</strong> Hum. Molec. Genet. 28: 1919-1929, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30715372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30715372</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30715372[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddz032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30715372">Hedberg-Oldfors et al. (2019)</a> knocked down the cardiac-specific zebrafish homolog of KLHL24, klhl24a, and observed defects in heart function at 48 hours postfertilization (hpf) that initially manifested as pericardial edema, alterations in heart rate, and reduced blood circulation. Ventricular failure and blocked blood circulation were observed at 72 hpf. Site-specific mutagenesis corresponding to the human mutations E350X and R306H (see MOLECULAR GENETICS) gave rise to heart defects in more than 70% of embryos, and the mutant mRNA could not rescue the knockdown of endogenous klhl24a. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30715372" 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=611295[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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<strong>.0001 EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH SCARRING AND HAIR LOSS, WITH OR WITHOUT DILATED CARDIOMYOPATHY</strong>
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KLHL24, VAL2-MET29 DEL, 1A-G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886037956 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037956;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=rs886037956" 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=rs886037956" 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=RCV000258014 OR RCV000415556 OR RCV000493863 OR RCV004758678" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000258014, RCV000415556, RCV000493863, RCV004758678" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000258014...</a>
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<p>In 3 unrelated Han Chinese individuals with generalized epidermolysis bullosa simplex (EBS6; <a href="/entry/617294">617294</a>), <a href="#6" class="mim-tip-reference" title="Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others. <strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong> Nature Genet. 48: 1508-1516, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>] [<a href="https://doi.org/10.1038/ng.3701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27798626">Lin et al. (2016)</a> identified heterozygosity for a de novo c.1A-G transition (c.1A-G, NM_017644.3) in the start codon of the KLHL24 gene, resulting in abolition of translation initiation at met1. Analysis of transfected HEK293T cells showed that the mutation resulted in an N-terminally truncated protein lacking the first 28 amino acids and demonstrated that met29 serves as an alternative initiation site (val2_met29del). The mutation was not found in the unaffected parents of the probands, in in-house databases, or in the dbSNP, 1000 Genomes Project, NHLBI Exome Variant Server, or ExAC databases. One of the patients (patient 1) had an affected daughter who died soon after birth due to large areas of skin denudation and secondary infection. The presence of cardiomyopathy was not mentioned for patient 1, who was 25 years old. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27798626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected individuals from 9 unrelated families with generalized EBS, including including 5 from Germany (families A, C, D, G, and H), 1 from Finland (family F), 1 from Switzerland (family B), 1 from Italy (family J), and 1 from Qatar (family I), <a href="#3" class="mim-tip-reference" title="He, Y., Maier, K., Leppert, J., Hausser, I., Schwieger-Briel, A., Weibel, L., Theiler, M., Kiritsi, D., Busch, H., Boerries, M., Hannula-Jouppi, K., Heikkila, H., Tasanen, K., Castiglia, D., Zambruno, G., Has, C. <strong>Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.</strong> Am. J. Hum. Genet. 99: 1395-1404, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889062</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27889062[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.2016.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889062">He et al. (2016)</a> identified heterozygosity for the recurrent c.1A-G transition in the KLHL24 gene. Recombinant expression of normal and mutant KLHL24 confirmed that the c.1A-G mutation resulted in translation of a truncated peptide, suggesting that met29 was used for the initiation of translation. The mutation segregated fully with disease in each of the families, and was not found in the dbSNP, 1000 Genomes, Exome Variant Server, or ExAC databases. Autosomal dominant inheritance was demonstrated in 3 of the families, including a Swiss father and 2 daughters, a German mother and daughter, and an Italian father and son. An 43-year-old male from the Italian family, JII.2, was reported to have dilated cardiomyopathy. Functional analysis indicated that autoubiquitination is abolished with the KLHL24 mutant, resulting in enhanced protein stability and higher abundance. After identifying KRT14 (<a href="/entry/148066">148066</a>) as a candidate ubiquitination substrate of KLHL24, the authors demonstrated dramatically lower KRT14 levels in patient skin samples compared to controls. They concluded that KLHL24 is an E3 ligase for KRT14 and that the start codon variants observed in EBS6 patients result in gain-of-function, inducing excessive ubiquitination and degradation of KRT14, resulting in KRT14 loss and skin fragility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27889062" 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 Dutch family in which a father and son had EBS, and the father also experienced severe dilated cardiomyopathy requiring transplantation at age 19 years, <a href="#11" class="mim-tip-reference" title="Yenamandra, V. K., van den Akker, P. C., Lemmink, H. H., Jan, S. Z., Diercks, G. F. H., Vermeer, M., van den Berg, M. P., van der Meer, P., Pasmooij, A. M. G., Sinke, R. J., Jonkman, M. F., Bolling, M. C. <strong>Cardiomyopathy in patients with epidermolysis bullosa simplex with mutations in KLHL24.</strong> Brit. J. Derm. 179: 1181-1183, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29779254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29779254</a>] [<a href="https://doi.org/10.1111/bjd.16797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29779254">Yenamandra et al. (2018)</a> identified heterozygosity for the previously reported recurrent c.1A-G mutation in the KLHL24 gene. The 14-year-old son showed a borderline enlarged left ventricle on echocardiography. The mutation was not found in the boy's unaffected sister. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29779254" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Schwieger-Briel, A., Fuentes, I., Castiglia, D., Barbato, A., Greutmann, M., Leppert, J., Duchatelet, S., Hovnanian, A., Burattini, S., Yubero, M. J., Ibanez-Arenas, R., Rebolledo-Jaramillo, B., and 9 others. <strong>Epidermolysis bullosa simplex with KLHL24 mutations is associated with dilated cardiomyopathy.</strong> J. Invest. Derm. 139: 244-249, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30120936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30120936</a>] [<a href="https://doi.org/10.1016/j.jid.2018.07.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30120936">Schwieger-Briel et al. (2019)</a> restudied families A, B, C, G, and J, originally reported by <a href="#3" class="mim-tip-reference" title="He, Y., Maier, K., Leppert, J., Hausser, I., Schwieger-Briel, A., Weibel, L., Theiler, M., Kiritsi, D., Busch, H., Boerries, M., Hannula-Jouppi, K., Heikkila, H., Tasanen, K., Castiglia, D., Zambruno, G., Has, C. <strong>Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.</strong> Am. J. Hum. Genet. 99: 1395-1404, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889062</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27889062[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.2016.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889062">He et al. (2016)</a>, and found that the patients exhibited evidence of cardiac involvement with either elevated cardiac biomarkers (affected individuals from all families) or documented dilated cardiomyopathy (the fathers in families B and J, at ages 34 and 45). <a href="#8" class="mim-tip-reference" title="Schwieger-Briel, A., Fuentes, I., Castiglia, D., Barbato, A., Greutmann, M., Leppert, J., Duchatelet, S., Hovnanian, A., Burattini, S., Yubero, M. J., Ibanez-Arenas, R., Rebolledo-Jaramillo, B., and 9 others. <strong>Epidermolysis bullosa simplex with KLHL24 mutations is associated with dilated cardiomyopathy.</strong> J. Invest. Derm. 139: 244-249, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30120936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30120936</a>] [<a href="https://doi.org/10.1016/j.jid.2018.07.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30120936">Schwieger-Briel et al. (2019)</a> also identified 2 more EBS probands (families 7 and 8) with the c.1A-G mutation in the KLHL24 gene. Both women had normal echocardiograms at ages 35 and 28; although the proband from family 7 reported a syncopal episode, she also had a seizure disorder of unknown origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30120936+27889062" 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>Noting that desmin (DES; <a href="/entry/125660">125660</a>) belongs to the same highly conserved family of intermediate filament proteins as keratins, <a href="#10" class="mim-tip-reference" title="Vermeer, M. C. S. C., Bolling, M. C., Bliley, J. M., Arevalo Gomez, K. F., Pavez-Giani, M. G., Kramer, D., Romero-Herrera, P. H., Westenbrink, B. D., Diercks, G. F. H., van den Berg, M. P., Feinberg, A. W., Sillje, H. H. W., van der Meer, P. <strong>Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues.</strong> J. Clin. Invest. 131: e140615, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34292882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34292882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34292882[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/10.1172/JCI140615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34292882">Vermeer et al. (2021)</a> performed immunofluorescence analysis of explanted heart tissue from the Dutch father with EBS and CMD originally described by <a href="#11" class="mim-tip-reference" title="Yenamandra, V. K., van den Akker, P. C., Lemmink, H. H., Jan, S. Z., Diercks, G. F. H., Vermeer, M., van den Berg, M. P., van der Meer, P., Pasmooij, A. M. G., Sinke, R. J., Jonkman, M. F., Bolling, M. C. <strong>Cardiomyopathy in patients with epidermolysis bullosa simplex with mutations in KLHL24.</strong> Brit. J. Derm. 179: 1181-1183, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29779254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29779254</a>] [<a href="https://doi.org/10.1111/bjd.16797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29779254">Yenamandra et al. (2018)</a>, and observed lower desmin intensity than that of other diseased heart explants. <a href="#10" class="mim-tip-reference" title="Vermeer, M. C. S. C., Bolling, M. C., Bliley, J. M., Arevalo Gomez, K. F., Pavez-Giani, M. G., Kramer, D., Romero-Herrera, P. H., Westenbrink, B. D., Diercks, G. F. H., van den Berg, M. P., Feinberg, A. W., Sillje, H. H. W., van der Meer, P. <strong>Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues.</strong> J. Clin. Invest. 131: e140615, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34292882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34292882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34292882[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/10.1172/JCI140615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34292882">Vermeer et al. (2021)</a> generated 3D dynamically loaded engineered heart tissues (dyn-EHTs) from human-induced pluripotent stem cell-derived cardiomyocytes from the Dutch father and his affected son, and confirmed 10-fold lower desmin levels in patient dyn-EHTs than in controls. In addition, the patient dyn-EHTs exhibited tissue dilatation, impaired mitochondrial function, decreased force values, and increased cardiomyocyte stress. HEK293 transfection studies confirmed KLHL24-mediated desmin degradation, and KLHL24 RNA interference or direct desmin overexpression recovered desmin protein levels, restoring morphology and function in patient-derived dyn-EHTs. The authors concluded that the presence of the gain-of-function KLHL24 mutation in cardiomyocytes results in excessive degradation of desmin, affecting tissue morphology and function, which can be prevented by restoring desmin protein levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=29779254+34292882" 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>.0002 EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH SCARRING AND HAIR LOSS</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">rs886037957 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037957;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=rs886037957" 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=rs886037957" 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 7-year-old Han Chinese boy with generalized epidermolysis bullosa simplex (EBS6; <a href="/entry/617294">617294</a>), <a href="#6" class="mim-tip-reference" title="Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others. <strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong> Nature Genet. 48: 1508-1516, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>] [<a href="https://doi.org/10.1038/ng.3701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27798626">Lin et al. (2016)</a> identified heterozygosity for a de novo c.3G-T transversion (c.3G-T, NM_017644.3) in the start codon of the KLHL gene, resulting in abolition of translation initiation at met1. Analysis of transfected HEK293T cells showed that the mutation resulted in an N-terminally truncated protein lacking the first 28 amino acids and demonstrated that met29 serves as an alternative initiation site (val2_met29del). The mutation was not found in his unaffected parents, in in-house databases, or in the dbSNP, 1000 Genomes Project, NHLBI Exome Variant Server, or ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27798626" 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>.0003 EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH SCARRING AND HAIR LOSS</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">rs886037957 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037957;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=rs886037957" 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=rs886037957" 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 5-year-old Israeli Jewish boy with generalized epidermolysis bullosa simplex (EBS6; <a href="/entry/617294">617294</a>), <a href="#6" class="mim-tip-reference" title="Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others. <strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong> Nature Genet. 48: 1508-1516, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>] [<a href="https://doi.org/10.1038/ng.3701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27798626">Lin et al. (2016)</a> identified heterozygosity for a de novo c.3G-A transition (c.3G-A, NM_017644.3) in the start codon of the KLHL gene, resulting in abolition of translation initiation at met1. Analysis of transfected HEK293T cells showed that the mutation resulted in an N-terminally truncated protein lacking the first 28 amino acids and demonstrated that met29 serves as an alternative initiation site (val2_met29del). The mutation was not found in his unaffected parents, in in-house databases, or in the dbSNP, 1000 Genomes Project, NHLBI Exome Variant Server, or ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27798626" 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 Italian girl (case 2) with EBS, <a href="#1" class="mim-tip-reference" title="El Hachem, M., Barresi, S., Diociaiuti, A., Boldrini, R., Condorelli, A. G., Capoluongo, E., Proto, V., Scuvera, G., Has, C., Tartaglia, M., Castiglia, D. <strong>Phenotypic features of epidermolysis bullosa simplex due to KLHL24 mutations in 3 Italian cases.</strong> Acta Derm. Venereol. 99: 238-239, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30226531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30226531</a>] [<a href="https://doi.org/10.2340/00015555-3046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30226531">El Hachem et al. (2019)</a> identified heterozygosity for the c.3G-A transition in the KLHL24 gene. Cardiac evaluation, including screening for cardiomyopathy markers, was normal, but the authors noted that due to her young age, future cardiac complications could not be excluded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30226531" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH SCARRING AND HAIR LOSS</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">rs1057515580 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057515580;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=rs1057515580" 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=rs1057515580" 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=RCV000408918 OR RCV000415575" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000408918, RCV000415575" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000408918...</a>
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<p>In a 4-year-old Swiss boy with generalized epidermolysis bullosa simplex (EBS6; <a href="/entry/617294">617294</a>), <a href="#3" class="mim-tip-reference" title="He, Y., Maier, K., Leppert, J., Hausser, I., Schwieger-Briel, A., Weibel, L., Theiler, M., Kiritsi, D., Busch, H., Boerries, M., Hannula-Jouppi, K., Heikkila, H., Tasanen, K., Castiglia, D., Zambruno, G., Has, C. <strong>Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.</strong> Am. J. Hum. Genet. 99: 1395-1404, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889062</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27889062[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.2016.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889062">He et al. (2016)</a> identified heterozygosity for a de novo c.2T-C transition (c.2T-C, NM_017644.3) in the start codon of the KLHL gene, resulting in abolition of translation initiation at met1. Recombinant expression of normal and mutant KLHL24 confirmed that the c.2T-C mutation resulted in translation of a truncated peptide, suggesting that met29 was used for the initiation of translation (val2_met29del). The mutation was not found in his unaffected parents or an unaffected brother, or in the dbSNP, 1000 Genomes, Exome Variant Server, or ExAC Browser databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27889062" 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 2 Italian boys with EBS, a 7-year-old (patient 1) and an infant (patient 3), <a href="#1" class="mim-tip-reference" title="El Hachem, M., Barresi, S., Diociaiuti, A., Boldrini, R., Condorelli, A. G., Capoluongo, E., Proto, V., Scuvera, G., Has, C., Tartaglia, M., Castiglia, D. <strong>Phenotypic features of epidermolysis bullosa simplex due to KLHL24 mutations in 3 Italian cases.</strong> Acta Derm. Venereol. 99: 238-239, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30226531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30226531</a>] [<a href="https://doi.org/10.2340/00015555-3046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30226531">El Hachem et al. (2019)</a> identified heterozygosity for the c.3G-A transition in the KLHL24 gene. The mutation was shown to have arisen de novo in both probands. Cardiac evaluation, including screening for cardiomyopathy markers, was normal in both, but the authors noted that due to their young ages, future cardiac complications could not be excluded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30226531" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Variant Function</em></strong></p><p>
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<a href="#7" class="mim-tip-reference" title="Logli, E., Marzuolo, E., D'Agostino, M., Conti, L. A., Lena, A. M., Diociaiuti, A., Dellambra, E., Has, C., Cianfanelli, V., Zambruno, G., El Hachem, M., Magenta, A., Candi, E., Condorelli, A. G. <strong>Proteasome-mediated degradation of keratins 7, 8, 17 and 18 by mutant KLHL24 in a foetal keratinocyte model: novel insight in congenital skin defects and fragility of epidermolysis bullosa simplex with cardiomyopathy.</strong> Hum. Molec. Genet. 31: 1308-1324, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34740256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34740256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34740256[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddab318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34740256">Logli et al. (2022)</a> studied primary keratinocytes from a 7-year-old boy (PT-1) with EBS, originally described by <a href="#1" class="mim-tip-reference" title="El Hachem, M., Barresi, S., Diociaiuti, A., Boldrini, R., Condorelli, A. G., Capoluongo, E., Proto, V., Scuvera, G., Has, C., Tartaglia, M., Castiglia, D. <strong>Phenotypic features of epidermolysis bullosa simplex due to KLHL24 mutations in 3 Italian cases.</strong> Acta Derm. Venereol. 99: 238-239, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30226531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30226531</a>] [<a href="https://doi.org/10.2340/00015555-3046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30226531">El Hachem et al. (2019)</a> as case 1, and a 7-year-old girl (PT-2) with EBS carrying the same c.2T-C mutation. Immunofluorescence antigen mapping of patient skin showed normal expression of major keratinocyte adhesion proteins, including K14 (KRT14; <a href="/entry/148066">148066</a>) and K5 (KRT5; <a href="/entry/148040">148040</a>), but confocal microscopy showed disorganization of the K14 network with focal areas of reduced K14 staining. <a href="#7" class="mim-tip-reference" title="Logli, E., Marzuolo, E., D'Agostino, M., Conti, L. A., Lena, A. M., Diociaiuti, A., Dellambra, E., Has, C., Cianfanelli, V., Zambruno, G., El Hachem, M., Magenta, A., Candi, E., Condorelli, A. G. <strong>Proteasome-mediated degradation of keratins 7, 8, 17 and 18 by mutant KLHL24 in a foetal keratinocyte model: novel insight in congenital skin defects and fragility of epidermolysis bullosa simplex with cardiomyopathy.</strong> Hum. Molec. Genet. 31: 1308-1324, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34740256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34740256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34740256[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddab318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34740256">Logli et al. (2022)</a> observed accelerated clonal conversion with reduced colony-forming efficiency (CFE) and early replicative senescence in patient keratinocytes compared to those from age-matched controls, and noted that these senescent features of EBS6 keratinocytes correlated with the skin atrophy seen in patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=34740256+30226531" 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 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 29, WITH POLYGLUCOSAN BODIES</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003152371" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003152371" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003152371</a>
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<p>In an Iraqi brother and sister (family A) with hypertrophic cardiomyopathy (CMH29; <a href="/entry/620236">620236</a>), <a href="#4" class="mim-tip-reference" title="Hedberg-Oldfors, C., Abramsson, A., Osborn, D. P. S., Danielsson, O., Fazlinezhad, A., Nilipour, Y., Hubbert, L., Nennesmo, I., Visuttijai, K., Bharj, J., Petropoulou, E., Shoreim, A., and 12 others. <strong>Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24.</strong> Hum. Molec. Genet. 28: 1919-1929, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30715372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30715372</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30715372[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddz032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30715372">Hedberg-Oldfors et al. (2019)</a> identified homozygosity for a c.1048G-T transversion (c.1048G-T, NM_017644.3) in exon 4 of the KLHL24 gene, resulting in a glu350-to-ter (E350X) substitution at the start of the kelch repeat domain. Their unaffected consanguineous parents were heterozygous for the mutation, which was not found in the Greater Middle Eastern Variome database. Site-specific mutagenesis corresponding to the E350X variant in zebrafish gave rise to heart defects in more than 70% of embryos, and the mutant mRNA could not rescue the knockdown of endogenous klhl24a. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30715372" 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 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 29, WITH POLYGLUCOSAN BODIES</strong>
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<p>In 4 Iranian sibs and a female cousin (family B) with hypertrophic cardiomyopathy (CMH29; <a href="/entry/620236">620236</a>), <a href="#4" class="mim-tip-reference" title="Hedberg-Oldfors, C., Abramsson, A., Osborn, D. P. S., Danielsson, O., Fazlinezhad, A., Nilipour, Y., Hubbert, L., Nennesmo, I., Visuttijai, K., Bharj, J., Petropoulou, E., Shoreim, A., and 12 others. <strong>Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24.</strong> Hum. Molec. Genet. 28: 1919-1929, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30715372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30715372</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30715372[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddz032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30715372">Hedberg-Oldfors et al. (2019)</a> identified homozygosity for a c.917G-A transition (c.917G-A, NM_017644.3) in exon 3 of the KLHL24 gene, resulting in an arg306-to-his (R306H) substitution at a highly conserved residue. The unaffected parents in both branches of the family were heterozygous for the mutation, which was not found in 500 ethnically matched in-house exomes or in the Greater Middle Eastern Variome database. Site-specific mutagenesis corresponding to the R350H variant in zebrafish gave rise to heart defects in more than 70% of embryos, and the mutant mRNA could not rescue the knockdown of endogenous klhl24a. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30715372" 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 EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH SCARRING, HAIR LOSS, AND DILATED CARDIOMYOPATHY</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003152373" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003152373" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003152373</a>
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<p>In 8 affected members of a Chilean family (family 9) with epidermolysis bullosa simplex with mild to moderate alopecia and follicular atrophoderma (EBS6; <a href="/entry/617294">617294</a>), including 2 who had died of dilated cardiomyopathy (CMD), <a href="#8" class="mim-tip-reference" title="Schwieger-Briel, A., Fuentes, I., Castiglia, D., Barbato, A., Greutmann, M., Leppert, J., Duchatelet, S., Hovnanian, A., Burattini, S., Yubero, M. J., Ibanez-Arenas, R., Rebolledo-Jaramillo, B., and 9 others. <strong>Epidermolysis bullosa simplex with KLHL24 mutations is associated with dilated cardiomyopathy.</strong> J. Invest. Derm. 139: 244-249, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30120936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30120936</a>] [<a href="https://doi.org/10.1016/j.jid.2018.07.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30120936">Schwieger-Briel et al. (2019)</a> identified heterozygosity for a c.2T-G transversion in the translation initiation codon of the KLHL24 gene. All 6 living affected family members had elevated cardiac biomarkers, even the youngest, a 2-year-old boy; and 3 affected men, ages 25 to 33, had moderate to severe CMD with reduced left ventricular ejection fractions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30120936" 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 EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH SCARRING, HAIR LOSS, AND DILATED CARDIOMYOPATHY</strong>
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KLHL24, 1A-T
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003152374" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003152374" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003152374</a>
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<p>In a 14-year-old girl with epidermolysis bullosa simplex (EBS6; <a href="/entry/617294">617294</a>) and severe dilated cardiomyopathy requiring heart transplantation, <a href="#2" class="mim-tip-reference" title="Grilletta, E. A. <strong>Cardiac transplant for epidermolysis bullosa simplex with KLHL24 mutation-associated cardiomyopathy.</strong> JAAD Case Rep. 5: 912-914, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31649980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31649980</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31649980[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.jdcr.2019.08.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31649980">Grilletta (2019)</a> identified heterozygosity for a mutation in the initiation codon of KLHL24 (c.1A-T). Because she was adopted, familial segregation could not be ascertained. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31649980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<strong>REFERENCES</strong>
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<a id="El Hachem2019" class="mim-anchor"></a>
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El Hachem, M., Barresi, S., Diociaiuti, A., Boldrini, R., Condorelli, A. G., Capoluongo, E., Proto, V., Scuvera, G., Has, C., Tartaglia, M., Castiglia, D.
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<strong>Phenotypic features of epidermolysis bullosa simplex due to KLHL24 mutations in 3 Italian cases.</strong>
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Acta Derm. Venereol. 99: 238-239, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30226531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30226531</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30226531" 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/10.2340/00015555-3046" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
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<a id="Grilletta2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Grilletta, E. A.
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<strong>Cardiac transplant for epidermolysis bullosa simplex with KLHL24 mutation-associated cardiomyopathy.</strong>
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JAAD Case Rep. 5: 912-914, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31649980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31649980</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31649980[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=31649980" 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.jdcr.2019.08.009" target="_blank">Full Text</a>]
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<a id="He2016" class="mim-anchor"></a>
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<div class="">
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He, Y., Maier, K., Leppert, J., Hausser, I., Schwieger-Briel, A., Weibel, L., Theiler, M., Kiritsi, D., Busch, H., Boerries, M., Hannula-Jouppi, K., Heikkila, H., Tasanen, K., Castiglia, D., Zambruno, G., Has, C.
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<strong>Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.</strong>
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Am. J. Hum. Genet. 99: 1395-1404, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889062</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27889062[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=27889062" 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.2016.11.005" target="_blank">Full Text</a>]
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<a id="Hedberg-Oldfors2019" class="mim-anchor"></a>
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<div class="">
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Hedberg-Oldfors, C., Abramsson, A., Osborn, D. P. S., Danielsson, O., Fazlinezhad, A., Nilipour, Y., Hubbert, L., Nennesmo, I., Visuttijai, K., Bharj, J., Petropoulou, E., Shoreim, A., and 12 others.
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<strong>Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24.</strong>
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Hum. Molec. Genet. 28: 1919-1929, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30715372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30715372</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30715372[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=30715372" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddz032" target="_blank">Full Text</a>]
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<a id="Laezza2007" class="mim-anchor"></a>
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Laezza, F., Wilding, T. J., Sequeira, S., Coussen, F., Zhang, X. Z., Hill-Robinson, R., Mulle, C., Huettner, J. E., Craig, A. M.
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<strong>KRIP6: a novel BTB/kelch protein regulating function of kainate receptors.</strong>
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Molec. Cell. Neurosci. 34: 539-550, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17254796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17254796</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17254796[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=17254796" 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.mcn.2006.12.003" target="_blank">Full Text</a>]
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<a id="Lin2016" class="mim-anchor"></a>
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Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others.
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<strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong>
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Nature Genet. 48: 1508-1516, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27798626" 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/ng.3701" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Logli2022" class="mim-anchor"></a>
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<div class="">
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Logli, E., Marzuolo, E., D'Agostino, M., Conti, L. A., Lena, A. M., Diociaiuti, A., Dellambra, E., Has, C., Cianfanelli, V., Zambruno, G., El Hachem, M., Magenta, A., Candi, E., Condorelli, A. G.
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<strong>Proteasome-mediated degradation of keratins 7, 8, 17 and 18 by mutant KLHL24 in a foetal keratinocyte model: novel insight in congenital skin defects and fragility of epidermolysis bullosa simplex with cardiomyopathy.</strong>
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Hum. Molec. Genet. 31: 1308-1324, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34740256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34740256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34740256[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=34740256" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddab318" target="_blank">Full Text</a>]
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<a id="Schwieger-Briel2019" class="mim-anchor"></a>
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<div class="">
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Schwieger-Briel, A., Fuentes, I., Castiglia, D., Barbato, A., Greutmann, M., Leppert, J., Duchatelet, S., Hovnanian, A., Burattini, S., Yubero, M. J., Ibanez-Arenas, R., Rebolledo-Jaramillo, B., and 9 others.
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<strong>Epidermolysis bullosa simplex with KLHL24 mutations is associated with dilated cardiomyopathy.</strong>
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J. Invest. Derm. 139: 244-249, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30120936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30120936</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30120936" 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.jid.2018.07.022" target="_blank">Full Text</a>]
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<a id="Scott2007" class="mim-anchor"></a>
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<div class="">
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Scott, A. F.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 7/31/2007.
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<a id="Vermeer2021" class="mim-anchor"></a>
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Vermeer, M. C. S. C., Bolling, M. C., Bliley, J. M., Arevalo Gomez, K. F., Pavez-Giani, M. G., Kramer, D., Romero-Herrera, P. H., Westenbrink, B. D., Diercks, G. F. H., van den Berg, M. P., Feinberg, A. W., Sillje, H. H. W., van der Meer, P.
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<strong>Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues.</strong>
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J. Clin. Invest. 131: e140615, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34292882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34292882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34292882[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=34292882" 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/10.1172/JCI140615" target="_blank">Full Text</a>]
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<a id="Yenamandra2018" class="mim-anchor"></a>
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Yenamandra, V. K., van den Akker, P. C., Lemmink, H. H., Jan, S. Z., Diercks, G. F. H., Vermeer, M., van den Berg, M. P., van der Meer, P., Pasmooij, A. M. G., Sinke, R. J., Jonkman, M. F., Bolling, M. C.
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<strong>Cardiomyopathy in patients with epidermolysis bullosa simplex with mutations in KLHL24.</strong>
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Brit. J. Derm. 179: 1181-1183, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29779254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29779254</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29779254" 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/bjd.16797" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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Marla J. F. O'Neill - updated : 02/08/2023
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 02/01/2023<br>Marla J. F. O'Neill - updated : 01/12/2017
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Creation Date:
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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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Alan F. Scott : 8/3/2007
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carol : 04/20/2023
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alopez : 02/08/2023<br>alopez : 02/01/2023<br>alopez : 10/29/2021<br>alopez : 01/12/2017<br>terry : 08/03/2007<br>carol : 8/3/2007
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<span class="mim-font">
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<strong>*</strong> 611295
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KELCH-LIKE 24; KLHL24
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<em>Alternative titles; symbols</em>
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KAINATE RECEPTOR-INTERACTING PROTEIN FOR GLUR6; KRIP6
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<strong><em>HGNC Approved Gene Symbol: KLHL24</em></strong>
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Cytogenetic location: 3q27.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:183,635,623-183,684,519 </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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<strong>Gene-Phenotype Relationships</strong>
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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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3q27.1
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Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies
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<span class="mim-font">
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620236
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Autosomal recessive
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3
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Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy
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617294
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Autosomal dominant
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>KLHL24 is a member of the Kelch-like protein family, which act as substrate-specific adaptors to cullin (see 603134) E3 ubiquitin ligases and which are involved in a variety of cellular processes such as cytoskeletal organization, regulation of cell morphology, cell migration, protein degradation, and gene expression (summary by Hedberg-Oldfors et al., 2019). </p>
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<strong>Cloning and Expression</strong>
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<p>Laezza et al. (2007) used the C-terminal domain of GluR6 (138244), a kainate receptor found at synapses in the central nervous system, as bait in a yeast 2-hybrid screen of a rat forebrain cDNA library and identified a novel protein, KLHL24, which they called KRIP6. KLHL24 contains a BTB/POZ domain near the N-terminus followed by a BACK domain and 6 consecutive kelch repeats. The BTB/POZ domain is a zinc finger and protein-protein dimerization domain. The BACK domain is similar to substrate-specific adaptors for protein ubiquitination, and the 6 kelch repeats likely form a beta-propeller structure. In situ hybridization and immunohistochemistry experiments showed that KLHL24 is widely expressed in rat brain, particularly in the cortex and hippocampus where expression of GluR6 is also prominent. </p><p>By RT-PCR, Lin et al. (2016) detected ubiquitous expression of human KLHL24 in representative adult tissues, including skin. Immunoprecipitation analysis of mouse skin and cerebral tissue was consistent with previous reports that Klhl24 is expressed at higher levels in the cerebral cortex than in skin. </p><p>He et al. (2016) used RT-PCR in human skin and skin cells and found expression of KLHL24 in all main skin cell types, including keratinocytes, dermal fibroblasts, and melanocytes. By immunofluorescence staining, KLHL24 was detected intracellularly and at the cell periphery, where it partially colocalized with desmoplakin (DSP; 125647) and E-cadherin (CDH1; 192090). </p><p>Yenamandra et al. (2018) performed immunofluorescence antigen mapping on human embryonic stem cell-derived cardiomyocytes and observed clear positive staining of KLHL24 along the cell membrane. The authors noted that the distribution pattern was similar to that of other intercalated disc proteins involved in cardiocutaneous syndromes. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>Scott (2007) mapped the KLHL24 gene to chromosome 3q27.1 based on an alignment of the KLHL24 sequence (GenBank AC068769) with the genomic sequence (build 36.2).</p>
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<strong>Gene Function</strong>
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<p>Laezza et al. (2007) confirmed interaction between KLHL24 and GluR6 in vivo through coexpression of epitope-tagged KLHL24 with GluR6 in COS-7 cells. The 2 proteins colocalized in a perinuclear pattern. Coimmunoprecipitation experiments also showed that the 2 proteins interact. Coexpression of KLHL24 and GluR6 changed currents observed in patch-clamp experiments, suggesting that binding of KLHL24 to GluR6 alters channel operation. Overexpression of KLHL24 reduced endogenous kainate receptor-mediated responses evoked in hippocampal neurons. Laezza et al. (2007) speculated that high levels of KLHL24 might protect neurons during high frequency release of glutamate by inhibiting peak current mediated by kainate receptors. </p><p>In mouse keratinocytes, Lin et al. (2016) observed that mRNA levels of Klhl24 increased significantly during differentiation, to a degree similar to that of the keratinocyte differentiation markers Lor (152445) and Krt10 (148080). In addition, Krt14 (148066) protein levels significantly decreased upon differentiation, with slightly increased mRNA levels, suggesting protein degradation. Expression of increasing amounts of KLHL24 in HEK293T cells resulted in a concomitant dose-dependent decrease in KRT14 abundance, and knockdown of KLHL24 in HaCaT cells markedly increased KRT14 protein levels. FISH assay of human skin samples from both patients (see MOLECULAR GENETICS) and controls showed lower KLHL24 expression in basal-layer keratinocytes than suprabasal keratinocytes, a pattern opposite to that of KRT14 expression. Lin et al. (2016) noted that the inverse correlation of KLHL24 mRNA levels and KRT14 protein levels in both human and mouse keratinocytes was consistent with a model in which KLHL24 functions as an E3 ligase for KRT14 ubiquitination and degradation, suggesting that KLHL24 has a role in the loss of KRT14 during keratinocyte differentiation. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p><strong><em>Epidermolysis Bullosa Simplex 6, with Scarring and Hair Loss, with or without Dilated Cardiomyopathy</em></strong></p><p>
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In 5 unrelated patients with generalized epidermolysis bullosa simplex with scarring and hair loss (EBS6; 617294), Lin et al. (2016) identified heterozygosity for mutations in the start codon of the KLHL24 gene (611295.0001-611295.0003). Analysis of transfected HEK293T cells showed that all 3 mutations resulted in an N-terminally truncated protein lacking the first 28 amino acids, and that met29 serves as an alternative initiation site. Although patient mRNA levels were comparable to control, transfection studies in HaCaT cells showed markedly higher protein levels for the mutant compared to wildtype; further experiments indicated that autoubiquitination is abolished with the KLHL24 mutant, resulting in enhanced protein stability and higher abundance. After identifying KRT14 as a candidate ubiquitination substrate of KLHL24, the authors observed dramatically lower KRT14 levels in patient skin samples compared to controls and noted that KRT5 (148040) levels were also lower than in controls. Lin et al. (2016) concluded that KLHL24 is an E3 ligase for KRT14 and that these gain-of-function variants induce excessive ubiquitination and degradation of KRT14, resulting in KRT14 loss and skin fragility. </p><p>In 10 unrelated families with generalized EBS, He et al. (2016) identified heterozygosity for mutations in the start codon of KLHL24; affected individuals from 9 of the families had the recurrent c.1A-G mutation (611295.0001), and 1 patient had a c.2T-C transition (611295.0004). RT-PCR of patient keratinocytes showed that the mutations did not result in reduced transcription or in mRNA decay; however, immunostaining showed a reduction of KLHL24 signal in the cytoplasm and at the cell periphery compared to control keratinocytes. In cultured patient keratinocytes, KRT14 staining appeared disorganized, irregular, and fragmented, whereas KRT5, tubulin, and actin were not significantly changed. In heat-stressed patient keratinocytes, KRT14 abnormalities were even more pronounced, with perinuclear distribution and fragmentation, suggesting increased depolymerization after stress induction, whereas control cells changed very little. In addition, the overall abundance of ubiquitinated proteins increased in control cells after heat stress, but did not change significantly in patient cells. Noting augmented phosphorylation of the stress-activated kinase p38 (see 600289) and a 2-fold increase in apoptosis in mutant keratinocytes, He et al. (2016) suggested that ubiquitination and subsequent proteasomal degradation of KRT14 might be disturbed in the presence of KLHL24 mutations, resulting in cellular stress and apoptosis. Immunoblotting showed amounts of KRT5 and KRT14 that were 1.5- to 2-fold higher in cell lysates from mutant keratinocytes than from controls, and KRT15 (148030) was also strongly upregulated in patient skin and keratinocytes compared to controls. In contrast to the findings by Lin et al. (2016), He et al. (2016) observed that while recombinant overexpression of normal KLHL24 in HaCaT keratinocytes promoted KRT14 degradation, mutant KLHL24 showed less activity than the wildtype molecule. The latter authors concluded that KLHL24 mutations cause skin fragility, and that KLHL24 plays a role in maintaining the balance between intermediate filament stability and degradation required for skin integrity. </p><p>In a Dutch family in which a father and son had EBS, with the father also showing dilated cardiomyopathy (CMD) and the 14-year-old son showing a borderline enlarged left ventricle, Yenamandra et al. (2018) identified heterozygosity for the recurrent c.1A-G mutation in the KLHL24 gene. In experiments using 3D cardiac tissue engineered from pluripotent stem cells derived from the Dutch father and son, Vermeer et al. (2021) demonstrated that the presence of the gain-of-function KLHL24 mutation in cardiomyocytes results in excessive degradation of desmin (DES; 125660), affecting tissue morphology and function, which could be prevented by restoring desmin protein levels. </p><p>Schwieger-Briel et al. (2019) restudied 10 patients with EBS6 and the c.1A-G mutation from 6 families that were previously reported by He et al. (2016), and found that the patients exhibited evidence of cardiac involvement with either elevated cardiac biomarkers or documented CMD. Schwieger-Briel et al. (2019) also identified 2 more EBS probands with the KLHL24 c.1A-G mutation; both women had normal echocardiograms at ages 35 and 28, although 1 proband reported a syncopal episode. In addition, the authors studied a Chilean family in which 8 members had EBS and were heterozygous for a different mutation in the translation initiation codon of KLHL24 (c.2T-G; 611295.0007); all 6 living members had elevated cardiac biomarkers, and 3 had documented CMD, and 2 family members had died a 'cardiac death' with CMD by history. Whole-exome sequencing and multigene panel data showed no pathogenic variants in known CMD-associated genes. </p><p>El Hachem et al. (2019) reported 3 children with EBS and heterozygosity for de novo mutations in the start codon of the KLHL24 gene: 2 boys, a 7-year-old and an infant, were heterozygous for the c.2T-C variant (611295.0004), and a 5-year-old girl was heterozygous for the c.3G-A variant (611295.0003). Cardiac evaluation, including screening for cardiomyopathy markers, was normal in all 3 of the children, although the authors noted that due to the young ages of the patients, possible future cardiac complications could not be excluded. </p><p>In a 14-year-old girl with EBS and severe CMD requiring heart transplantation, Grilletta (2019) analyzed a panel of EB-associated genes and identified heterozygosity for a mutation in the initiation codon of KLHL24 (c.1A-T; 611295.0008). Because she was adopted, familial segregation could not be ascertained. </p><p><strong><em>Familial Hypertrophic Cardiomyopathy 29 with Polyglucosan Bodies</em></strong></p><p>
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In 2 unrelated families segregating autosomal recessive hypertrophic cardiomyopathy (CMH29; 620236), Hedberg-Oldfors et al. (2019) identified homozygosity for mutations in the KLHL24 gene: in family A, of Iraqi origin, an affected brother and sister were homozygous for a nonsense mutation (E350X; 611295.0005); and in family B, of Iranian origin, 4 sibs and an affected cousin were homozygous for a missense mutation (R306H; 611295.0006). The unaffected parents in both pedigrees were heterozygous for the respective mutations, neither of which was found in the Greater Middle Eastern Variome database. </p>
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<strong>Animal Model</strong>
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<span class="mim-text-font">
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<p>Lin et al. (2016) generated knockin mice with the KLHL24 c.3G-T mutation (611295.0002) and observed lower body weight, smaller body size, and more pronounced age-related hair loss than their wildtype littermates. Klhl24-null mice appeared grossly normal, and neither Klhl24-null mice or those carrying the c.3G-T variant showed signs of skin fragility. </p><p>Hedberg-Oldfors et al. (2019) knocked down the cardiac-specific zebrafish homolog of KLHL24, klhl24a, and observed defects in heart function at 48 hours postfertilization (hpf) that initially manifested as pericardial edema, alterations in heart rate, and reduced blood circulation. Ventricular failure and blocked blood circulation were observed at 72 hpf. Site-specific mutagenesis corresponding to the human mutations E350X and R306H (see MOLECULAR GENETICS) gave rise to heart defects in more than 70% of embryos, and the mutant mRNA could not rescue the knockdown of endogenous klhl24a. </p>
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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>8 Selected Examples):</strong>
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<p />
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<h4>
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<span class="mim-font">
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<strong>.0001 EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH SCARRING AND HAIR LOSS, WITH OR WITHOUT DILATED CARDIOMYOPATHY</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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KLHL24, VAL2-MET29 DEL, 1A-G
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<br />
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SNP: rs886037956,
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ClinVar: RCV000258014, RCV000415556, RCV000493863, RCV004758678
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 unrelated Han Chinese individuals with generalized epidermolysis bullosa simplex (EBS6; 617294), Lin et al. (2016) identified heterozygosity for a de novo c.1A-G transition (c.1A-G, NM_017644.3) in the start codon of the KLHL24 gene, resulting in abolition of translation initiation at met1. Analysis of transfected HEK293T cells showed that the mutation resulted in an N-terminally truncated protein lacking the first 28 amino acids and demonstrated that met29 serves as an alternative initiation site (val2_met29del). The mutation was not found in the unaffected parents of the probands, in in-house databases, or in the dbSNP, 1000 Genomes Project, NHLBI Exome Variant Server, or ExAC databases. One of the patients (patient 1) had an affected daughter who died soon after birth due to large areas of skin denudation and secondary infection. The presence of cardiomyopathy was not mentioned for patient 1, who was 25 years old. </p><p>In affected individuals from 9 unrelated families with generalized EBS, including including 5 from Germany (families A, C, D, G, and H), 1 from Finland (family F), 1 from Switzerland (family B), 1 from Italy (family J), and 1 from Qatar (family I), He et al. (2016) identified heterozygosity for the recurrent c.1A-G transition in the KLHL24 gene. Recombinant expression of normal and mutant KLHL24 confirmed that the c.1A-G mutation resulted in translation of a truncated peptide, suggesting that met29 was used for the initiation of translation. The mutation segregated fully with disease in each of the families, and was not found in the dbSNP, 1000 Genomes, Exome Variant Server, or ExAC databases. Autosomal dominant inheritance was demonstrated in 3 of the families, including a Swiss father and 2 daughters, a German mother and daughter, and an Italian father and son. An 43-year-old male from the Italian family, JII.2, was reported to have dilated cardiomyopathy. Functional analysis indicated that autoubiquitination is abolished with the KLHL24 mutant, resulting in enhanced protein stability and higher abundance. After identifying KRT14 (148066) as a candidate ubiquitination substrate of KLHL24, the authors demonstrated dramatically lower KRT14 levels in patient skin samples compared to controls. They concluded that KLHL24 is an E3 ligase for KRT14 and that the start codon variants observed in EBS6 patients result in gain-of-function, inducing excessive ubiquitination and degradation of KRT14, resulting in KRT14 loss and skin fragility. </p><p>In a Dutch family in which a father and son had EBS, and the father also experienced severe dilated cardiomyopathy requiring transplantation at age 19 years, Yenamandra et al. (2018) identified heterozygosity for the previously reported recurrent c.1A-G mutation in the KLHL24 gene. The 14-year-old son showed a borderline enlarged left ventricle on echocardiography. The mutation was not found in the boy's unaffected sister. </p><p>Schwieger-Briel et al. (2019) restudied families A, B, C, G, and J, originally reported by He et al. (2016), and found that the patients exhibited evidence of cardiac involvement with either elevated cardiac biomarkers (affected individuals from all families) or documented dilated cardiomyopathy (the fathers in families B and J, at ages 34 and 45). Schwieger-Briel et al. (2019) also identified 2 more EBS probands (families 7 and 8) with the c.1A-G mutation in the KLHL24 gene. Both women had normal echocardiograms at ages 35 and 28; although the proband from family 7 reported a syncopal episode, she also had a seizure disorder of unknown origin. </p><p>Noting that desmin (DES; 125660) belongs to the same highly conserved family of intermediate filament proteins as keratins, Vermeer et al. (2021) performed immunofluorescence analysis of explanted heart tissue from the Dutch father with EBS and CMD originally described by Yenamandra et al. (2018), and observed lower desmin intensity than that of other diseased heart explants. Vermeer et al. (2021) generated 3D dynamically loaded engineered heart tissues (dyn-EHTs) from human-induced pluripotent stem cell-derived cardiomyocytes from the Dutch father and his affected son, and confirmed 10-fold lower desmin levels in patient dyn-EHTs than in controls. In addition, the patient dyn-EHTs exhibited tissue dilatation, impaired mitochondrial function, decreased force values, and increased cardiomyocyte stress. HEK293 transfection studies confirmed KLHL24-mediated desmin degradation, and KLHL24 RNA interference or direct desmin overexpression recovered desmin protein levels, restoring morphology and function in patient-derived dyn-EHTs. The authors concluded that the presence of the gain-of-function KLHL24 mutation in cardiomyocytes results in excessive degradation of desmin, affecting tissue morphology and function, which can be prevented by restoring desmin protein levels. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH SCARRING AND HAIR LOSS</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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KLHL24, VAL2-MET29 DEL, 3G-T
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<br />
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SNP: rs886037957,
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ClinVar: RCV000258008, RCV000415601
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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 7-year-old Han Chinese boy with generalized epidermolysis bullosa simplex (EBS6; 617294), Lin et al. (2016) identified heterozygosity for a de novo c.3G-T transversion (c.3G-T, NM_017644.3) in the start codon of the KLHL gene, resulting in abolition of translation initiation at met1. Analysis of transfected HEK293T cells showed that the mutation resulted in an N-terminally truncated protein lacking the first 28 amino acids and demonstrated that met29 serves as an alternative initiation site (val2_met29del). The mutation was not found in his unaffected parents, in in-house databases, or in the dbSNP, 1000 Genomes Project, NHLBI Exome Variant Server, or ExAC databases. </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 EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH SCARRING AND HAIR LOSS</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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KLHL24, VAL2-MET29 DEL, 3G-A
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<br />
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SNP: rs886037957,
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ClinVar: RCV000258019, RCV000415529
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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 5-year-old Israeli Jewish boy with generalized epidermolysis bullosa simplex (EBS6; 617294), Lin et al. (2016) identified heterozygosity for a de novo c.3G-A transition (c.3G-A, NM_017644.3) in the start codon of the KLHL gene, resulting in abolition of translation initiation at met1. Analysis of transfected HEK293T cells showed that the mutation resulted in an N-terminally truncated protein lacking the first 28 amino acids and demonstrated that met29 serves as an alternative initiation site (val2_met29del). The mutation was not found in his unaffected parents, in in-house databases, or in the dbSNP, 1000 Genomes Project, NHLBI Exome Variant Server, or ExAC databases. </p><p>In a 5-year-old Italian girl (case 2) with EBS, El Hachem et al. (2019) identified heterozygosity for the c.3G-A transition in the KLHL24 gene. Cardiac evaluation, including screening for cardiomyopathy markers, was normal, but the authors noted that due to her young age, future cardiac complications could not be excluded. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH SCARRING AND HAIR LOSS</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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KLHL24, VAL2-MET29 DEL, 2T-C
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<br />
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SNP: rs1057515580,
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ClinVar: RCV000408918, RCV000415575
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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 4-year-old Swiss boy with generalized epidermolysis bullosa simplex (EBS6; 617294), He et al. (2016) identified heterozygosity for a de novo c.2T-C transition (c.2T-C, NM_017644.3) in the start codon of the KLHL gene, resulting in abolition of translation initiation at met1. Recombinant expression of normal and mutant KLHL24 confirmed that the c.2T-C mutation resulted in translation of a truncated peptide, suggesting that met29 was used for the initiation of translation (val2_met29del). The mutation was not found in his unaffected parents or an unaffected brother, or in the dbSNP, 1000 Genomes, Exome Variant Server, or ExAC Browser databases. </p><p>In 2 Italian boys with EBS, a 7-year-old (patient 1) and an infant (patient 3), El Hachem et al. (2019) identified heterozygosity for the c.3G-A transition in the KLHL24 gene. The mutation was shown to have arisen de novo in both probands. Cardiac evaluation, including screening for cardiomyopathy markers, was normal in both, but the authors noted that due to their young ages, future cardiac complications could not be excluded. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Logli et al. (2022) studied primary keratinocytes from a 7-year-old boy (PT-1) with EBS, originally described by El Hachem et al. (2019) as case 1, and a 7-year-old girl (PT-2) with EBS carrying the same c.2T-C mutation. Immunofluorescence antigen mapping of patient skin showed normal expression of major keratinocyte adhesion proteins, including K14 (KRT14; 148066) and K5 (KRT5; 148040), but confocal microscopy showed disorganization of the K14 network with focal areas of reduced K14 staining. Logli et al. (2022) observed accelerated clonal conversion with reduced colony-forming efficiency (CFE) and early replicative senescence in patient keratinocytes compared to those from age-matched controls, and noted that these senescent features of EBS6 keratinocytes correlated with the skin atrophy seen in patients. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 29, WITH POLYGLUCOSAN BODIES</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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KLHL24, GLU350TER
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<br />
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ClinVar: RCV003152371
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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 an Iraqi brother and sister (family A) with hypertrophic cardiomyopathy (CMH29; 620236), Hedberg-Oldfors et al. (2019) identified homozygosity for a c.1048G-T transversion (c.1048G-T, NM_017644.3) in exon 4 of the KLHL24 gene, resulting in a glu350-to-ter (E350X) substitution at the start of the kelch repeat domain. Their unaffected consanguineous parents were heterozygous for the mutation, which was not found in the Greater Middle Eastern Variome database. Site-specific mutagenesis corresponding to the E350X variant in zebrafish gave rise to heart defects in more than 70% of embryos, and the mutant mRNA could not rescue the knockdown of endogenous klhl24a. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0006 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 29, WITH POLYGLUCOSAN BODIES</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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KLHL24, ARG306HIS
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<br />
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ClinVar: RCV003152372
|
|
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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 4 Iranian sibs and a female cousin (family B) with hypertrophic cardiomyopathy (CMH29; 620236), Hedberg-Oldfors et al. (2019) identified homozygosity for a c.917G-A transition (c.917G-A, NM_017644.3) in exon 3 of the KLHL24 gene, resulting in an arg306-to-his (R306H) substitution at a highly conserved residue. The unaffected parents in both branches of the family were heterozygous for the mutation, which was not found in 500 ethnically matched in-house exomes or in the Greater Middle Eastern Variome database. Site-specific mutagenesis corresponding to the R350H variant in zebrafish gave rise to heart defects in more than 70% of embryos, and the mutant mRNA could not rescue the knockdown of endogenous klhl24a. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0007 EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH SCARRING, HAIR LOSS, AND DILATED CARDIOMYOPATHY</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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KLHL24, 2T-G
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<br />
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|
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ClinVar: RCV003152373
|
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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 8 affected members of a Chilean family (family 9) with epidermolysis bullosa simplex with mild to moderate alopecia and follicular atrophoderma (EBS6; 617294), including 2 who had died of dilated cardiomyopathy (CMD), Schwieger-Briel et al. (2019) identified heterozygosity for a c.2T-G transversion in the translation initiation codon of the KLHL24 gene. All 6 living affected family members had elevated cardiac biomarkers, even the youngest, a 2-year-old boy; and 3 affected men, ages 25 to 33, had moderate to severe CMD with reduced left ventricular ejection fractions. </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>.0008 EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH SCARRING, HAIR LOSS, AND DILATED CARDIOMYOPATHY</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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KLHL24, 1A-T
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<br />
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ClinVar: RCV003152374
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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 14-year-old girl with epidermolysis bullosa simplex (EBS6; 617294) and severe dilated cardiomyopathy requiring heart transplantation, Grilletta (2019) identified heterozygosity for a mutation in the initiation codon of KLHL24 (c.1A-T). Because she was adopted, familial segregation could not be ascertained. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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El Hachem, M., Barresi, S., Diociaiuti, A., Boldrini, R., Condorelli, A. G., Capoluongo, E., Proto, V., Scuvera, G., Has, C., Tartaglia, M., Castiglia, D.
|
|
<strong>Phenotypic features of epidermolysis bullosa simplex due to KLHL24 mutations in 3 Italian cases.</strong>
|
|
Acta Derm. Venereol. 99: 238-239, 2019.
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[PubMed: 30226531]
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[Full Text: https://doi.org/10.2340/00015555-3046]
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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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Grilletta, E. A.
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<strong>Cardiac transplant for epidermolysis bullosa simplex with KLHL24 mutation-associated cardiomyopathy.</strong>
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JAAD Case Rep. 5: 912-914, 2019.
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[PubMed: 31649980]
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[Full Text: https://doi.org/10.1016/j.jdcr.2019.08.009]
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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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He, Y., Maier, K., Leppert, J., Hausser, I., Schwieger-Briel, A., Weibel, L., Theiler, M., Kiritsi, D., Busch, H., Boerries, M., Hannula-Jouppi, K., Heikkila, H., Tasanen, K., Castiglia, D., Zambruno, G., Has, C.
|
|
<strong>Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.</strong>
|
|
Am. J. Hum. Genet. 99: 1395-1404, 2016.
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[PubMed: 27889062]
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[Full Text: https://doi.org/10.1016/j.ajhg.2016.11.005]
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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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Hedberg-Oldfors, C., Abramsson, A., Osborn, D. P. S., Danielsson, O., Fazlinezhad, A., Nilipour, Y., Hubbert, L., Nennesmo, I., Visuttijai, K., Bharj, J., Petropoulou, E., Shoreim, A., and 12 others.
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|
<strong>Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24.</strong>
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Hum. Molec. Genet. 28: 1919-1929, 2019.
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[PubMed: 30715372]
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[Full Text: https://doi.org/10.1093/hmg/ddz032]
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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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Laezza, F., Wilding, T. J., Sequeira, S., Coussen, F., Zhang, X. Z., Hill-Robinson, R., Mulle, C., Huettner, J. E., Craig, A. M.
|
|
<strong>KRIP6: a novel BTB/kelch protein regulating function of kainate receptors.</strong>
|
|
Molec. Cell. Neurosci. 34: 539-550, 2007.
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[PubMed: 17254796]
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[Full Text: https://doi.org/10.1016/j.mcn.2006.12.003]
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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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Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others.
|
|
<strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong>
|
|
Nature Genet. 48: 1508-1516, 2016.
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[PubMed: 27798626]
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[Full Text: https://doi.org/10.1038/ng.3701]
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</p>
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</li>
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<li>
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Logli, E., Marzuolo, E., D'Agostino, M., Conti, L. A., Lena, A. M., Diociaiuti, A., Dellambra, E., Has, C., Cianfanelli, V., Zambruno, G., El Hachem, M., Magenta, A., Candi, E., Condorelli, A. G.
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<strong>Proteasome-mediated degradation of keratins 7, 8, 17 and 18 by mutant KLHL24 in a foetal keratinocyte model: novel insight in congenital skin defects and fragility of epidermolysis bullosa simplex with cardiomyopathy.</strong>
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Hum. Molec. Genet. 31: 1308-1324, 2022.
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[PubMed: 34740256]
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[Full Text: https://doi.org/10.1093/hmg/ddab318]
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Schwieger-Briel, A., Fuentes, I., Castiglia, D., Barbato, A., Greutmann, M., Leppert, J., Duchatelet, S., Hovnanian, A., Burattini, S., Yubero, M. J., Ibanez-Arenas, R., Rebolledo-Jaramillo, B., and 9 others.
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<strong>Epidermolysis bullosa simplex with KLHL24 mutations is associated with dilated cardiomyopathy.</strong>
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J. Invest. Derm. 139: 244-249, 2019.
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[PubMed: 30120936]
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Scott, A. F.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 7/31/2007.
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Vermeer, M. C. S. C., Bolling, M. C., Bliley, J. M., Arevalo Gomez, K. F., Pavez-Giani, M. G., Kramer, D., Romero-Herrera, P. H., Westenbrink, B. D., Diercks, G. F. H., van den Berg, M. P., Feinberg, A. W., Sillje, H. H. W., van der Meer, P.
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<strong>Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues.</strong>
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J. Clin. Invest. 131: e140615, 2021.
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[PubMed: 34292882]
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[Full Text: https://doi.org/10.1172/JCI140615]
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Yenamandra, V. K., van den Akker, P. C., Lemmink, H. H., Jan, S. Z., Diercks, G. F. H., Vermeer, M., van den Berg, M. P., van der Meer, P., Pasmooij, A. M. G., Sinke, R. J., Jonkman, M. F., Bolling, M. C.
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<strong>Cardiomyopathy in patients with epidermolysis bullosa simplex with mutations in KLHL24.</strong>
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Brit. J. Derm. 179: 1181-1183, 2018.
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[PubMed: 29779254]
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[Full Text: https://doi.org/10.1111/bjd.16797]
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Marla J. F. O'Neill - updated : 02/08/2023<br>Marla J. F. O'Neill - updated : 02/01/2023<br>Marla J. F. O'Neill - updated : 01/12/2017
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