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<title>
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Entry
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- *615340 - KELCH-LIKE 40: KLHL40
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- OMIM
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</ul>
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</nav>
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
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<div class="form-group">
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<div class="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<li role="separator" class="divider"></li>
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<li>
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<a href="/history"> Search History </a>
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</ul>
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</div>
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</div>
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<div class="autocomplete" id="mimEntrySearchAutocomplete"></div>
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</div>
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</div>
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<span class="small">
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</form>
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<p />
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</div>
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<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
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<div id="mimAlertBanner">
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</div>
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</div>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*615340</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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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>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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</li>
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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>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
|
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<a href="/allelicVariants/615340">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
|
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
|
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
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<span class="panel-title">
|
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<span class="small">
|
|
<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=ENSG00000157119;t=ENST00000287777" 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=131377" 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=615340" 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=ENSG00000157119;t=ENST00000287777" 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_152393" 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_152393" 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=615340" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
|
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</div>
|
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</div>
|
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</div>
|
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
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</a>
|
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</span>
|
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</span>
|
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</div>
|
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.proteinatlas.org/search/KLHL40" 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/16552019,27803571,27883915,45593142,83405914,119585068,119585069,125950763,158256024,194374105" 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/Q2TBA0" 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=131377" 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=ENSG00000157119;t=ENST00000287777" 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=KLHL40" 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=KLHL40" 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+131377" 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/KLHL40" 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:131377" 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/131377" 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=ENST00000287777.5&hgg_start=42685537&hgg_end=42692544&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:30372" 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=615340[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=615340[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/KLHL40/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000157119" 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=KLHL40" 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=KLHL40" 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=KLHL40" 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=KLHL40&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/PA134908127" 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:30372" 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:1919580" 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/KLHL40#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:1919580" 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/131377/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=131377" 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-050916-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=KLHL40&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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615340
|
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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 40: KLHL40
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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>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
SARCOSYNAPSIN; SYRP<br />
|
|
KELCH REPEAT- AND BTB/POZ DOMAIN-CONTAINING PROTEIN 5; KBTBD5
|
|
</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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=KLHL40" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">KLHL40</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/3/208?start=-3&limit=10&highlight=208">3p22.1</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:42685537-42692544&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'})">3:42,685,537-42,692,544</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/3/208?start=-3&limit=10&highlight=208">
|
|
3p22.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Nemaline myopathy 8, autosomal recessive
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/615348"> 615348 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
</tr>
|
|
|
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|
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</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
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<p><a href="#3" class="mim-tip-reference" title="Ravenscroft, G., Miyatake, S., Lehtokari, V.-L., Todd, E. J., Vornanen, P., Yau, K. S., Hayashi, Y. K., Miyake, N., Tsurusaki, Y., Doi, H., Saitsu, H., Osaka, H., and 43 others. <strong>Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.</strong> Am. J. Hum. Genet. 93: 6-18, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23746549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23746549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23746549[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.2013.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23746549">Ravenscroft et al. (2013)</a> reported that the 621-amino acid KLHL40 protein has an N-terminal BTB/BACK domain and 5 C-terminal Kelch repeats predicted to form a beta-propeller structure. RT-PCR analysis of human tissues detected highest expression in adult skeletal muscle, with much lower expression in heart, and very weak expression in pancreas. No expression was detected in brain, placenta, lung, liver, and kidney. In human fetal tissues, KLHL40 was detected in striated muscle only. Western blot analysis of human skeletal muscle showed that KLHL40 was more abundant in fetal muscle than in postnatal muscle. Western blot analysis of mouse tissues detected Klhl40 in skeletal muscle only. Expression of Klhl40 increased with differentiation in cultured mouse C2C12 myoblasts. Immunohistochemical analysis of human fetal skeletal muscle localized KLHL40 to the A-band. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23746549" 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 Northern blot analysis of mouse tissues, <a href="#1" class="mim-tip-reference" title="Garg, A., O'Rourke, J., Long, C., Doering, J., Ravenscroft, G., Bezprozvannaya, S., Nelson, B. R., Beetz, N., Li, L., Chen, S., Laing, N. G., Grange, R. W., Bassel-Duby, R., Olson, E. N. <strong>KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy.</strong> J. Clin. Invest. 124: 3529-3539, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24960163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24960163</a>] [<a href="https://doi.org/10.1172/JCI74994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24960163">Garg et al. (2014)</a> detected high Klhl40 expression in skeletal muscle, lower expression in heart, and little to no expression in other tissues examined. Electroporation of flexor digitorum brevis of adult mice showed localization of fluorescence-tagged Klhl40 at both the I band and A band. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24960163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#3" class="mim-tip-reference" title="Ravenscroft, G., Miyatake, S., Lehtokari, V.-L., Todd, E. J., Vornanen, P., Yau, K. S., Hayashi, Y. K., Miyake, N., Tsurusaki, Y., Doi, H., Saitsu, H., Osaka, H., and 43 others. <strong>Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.</strong> Am. J. Hum. Genet. 93: 6-18, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23746549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23746549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23746549[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.2013.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23746549">Ravenscroft et al. (2013)</a> determined that the KLHL40 gene contains 6 coding exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23746549" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Hartz, P. A. <strong>Personal Communication.</strong> Baltimore, Md. 7/25/2013."None>Hartz (2013)</a> mapped the KLHL40 gene to chromosome 3p22.1 based on an alignment of the KLHL40 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AK056577" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AK056577</a>) with the genomic sequence (GRCh37).</p>
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<p><a href="#1" class="mim-tip-reference" title="Garg, A., O'Rourke, J., Long, C., Doering, J., Ravenscroft, G., Bezprozvannaya, S., Nelson, B. R., Beetz, N., Li, L., Chen, S., Laing, N. G., Grange, R. W., Bassel-Duby, R., Olson, E. N. <strong>KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy.</strong> J. Clin. Invest. 124: 3529-3539, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24960163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24960163</a>] [<a href="https://doi.org/10.1172/JCI74994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24960163">Garg et al. (2014)</a> found that, rather than promote proteasome-mediated protein degradation like other BTB-BACK-Kelch family proteins, mouse Klhl40 stabilized skeletal muscle Neb (<a href="/entry/161650">161650</a>) and Lmod3 (<a href="/entry/616112">616112</a>). Yeast 2-hybrid analysis of a human skeletal muscle cDNA library, followed by coimmunoprecipitation analysis, showed that Klhl40 interacted directly with NEB and LMOD3. In transfected COS7 cells, coexpression of Klhl40 stabilized NEB and LMOD3 proteins comparably to a proteasome inhibitor. Klhl40 reduced polyubiquitination of lys48 of LMOD3, which specifically marks a protein for proteasome-mediated degradation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24960163" 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>By whole-exome sequencing, <a href="#3" class="mim-tip-reference" title="Ravenscroft, G., Miyatake, S., Lehtokari, V.-L., Todd, E. J., Vornanen, P., Yau, K. S., Hayashi, Y. K., Miyake, N., Tsurusaki, Y., Doi, H., Saitsu, H., Osaka, H., and 43 others. <strong>Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.</strong> Am. J. Hum. Genet. 93: 6-18, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23746549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23746549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23746549[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.2013.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23746549">Ravenscroft et al. (2013)</a> identified homozygous or compound heterozygous mutations (see, e.g., <a href="#0001">615340.0001</a>-<a href="#0003">615340.0003</a>) in the KLHL40 gene in affected members from 6 families with autosomal recessive severe nemaline myopathy-8 (NEM8; <a href="/entry/615348">615348</a>). The mutations segregated with the disorder and were not found in several large control databases. Subsequent screening of KLHL40 by Sanger sequencing in additional probands with severe NEM resulted in the identification of a total of 19 variants in 28 (19.6%) of 143 families affected by severe NEM. There were 4 frameshifts, 12 missense mutations, 2 nonsense mutations, and 1 splice site mutation, and the mutations were scattered throughout all exons. One mutation (E528K; <a href="#0001">615340.0001</a>) was identified to be a founder mutation among Japanese individuals. Structural analysis of the missense mutations indicated that they would most likely destabilize bonds or hydrophobic cores, resulting in protein instability. In addition, 129 probands with a milder phenotype were screened, but no KLHL40 mutations were identified in this cohort, confirming that KLHL40 mutations are most likely exclusive to severe cases. The phenotype was severe and included fetal akinesia or hypokinesia and contractures, fractures, respiratory failure, and swallowing difficulties apparent at birth. The average age at death was 5 months. Skeletal muscle biopsy showed absence of KLHL40 even in patients with 2 missense mutations, consistent with a loss of function mechanism, and up to 20% of patients had virtually no normal myofibrils ('miliary NEM'). <a href="#3" class="mim-tip-reference" title="Ravenscroft, G., Miyatake, S., Lehtokari, V.-L., Todd, E. J., Vornanen, P., Yau, K. S., Hayashi, Y. K., Miyake, N., Tsurusaki, Y., Doi, H., Saitsu, H., Osaka, H., and 43 others. <strong>Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.</strong> Am. J. Hum. Genet. 93: 6-18, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23746549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23746549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23746549[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.2013.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23746549">Ravenscroft et al. (2013)</a> suggested that the KLHL40 gene should be screened in individuals with autosomal recessive NEM who present with prenatal symptoms and/or contractures, as well as in all Japanese individuals with severe NEM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23746549" 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 analyzing muscle samples from patients with nemalin myopathy and mutations in KLHL40, <a href="#1" class="mim-tip-reference" title="Garg, A., O'Rourke, J., Long, C., Doering, J., Ravenscroft, G., Bezprozvannaya, S., Nelson, B. R., Beetz, N., Li, L., Chen, S., Laing, N. G., Grange, R. W., Bassel-Duby, R., Olson, E. N. <strong>KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy.</strong> J. Clin. Invest. 124: 3529-3539, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24960163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24960163</a>] [<a href="https://doi.org/10.1172/JCI74994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24960163">Garg et al. (2014)</a> found that 2 patients with severe muscle pathology and complete deficiency of KLHL40 expression had marked reduction in LMOD3 and NEB. A third patient with less severe muscle pathology and residual KLHL40 had relatively normal LMOD3 and NEB content. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24960163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The zebrafish genome contains 2 orthologs of KLHL40, Klhl40a and Klhl40b. RT-PCR detected Klhl40a prominently expressed in larval zebrafish and in adult heart and skeletal muscle, with much weaker expression in adult eye, skin, and brain. Klhl40b was prominently expressed in larval zebrafish and in adult skeletal muscle, with weaker expression in adult eye. <a href="#3" class="mim-tip-reference" title="Ravenscroft, G., Miyatake, S., Lehtokari, V.-L., Todd, E. J., Vornanen, P., Yau, K. S., Hayashi, Y. K., Miyake, N., Tsurusaki, Y., Doi, H., Saitsu, H., Osaka, H., and 43 others. <strong>Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.</strong> Am. J. Hum. Genet. 93: 6-18, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23746549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23746549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23746549[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.2013.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23746549">Ravenscroft et al. (2013)</a> found that morpholino-mediated knockdown of both Klhl40 genes in zebrafish resulted in a curved trunk and small head, with disrupted muscle patterning, gaps between myofibers, and widened Z-disks. Knockdown of either or both Klhl40 genes in zebrafish caused sporadic muscle tremors and absence of coordinated swimming. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23746549" 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="Garg, A., O'Rourke, J., Long, C., Doering, J., Ravenscroft, G., Bezprozvannaya, S., Nelson, B. R., Beetz, N., Li, L., Chen, S., Laing, N. G., Grange, R. W., Bassel-Duby, R., Olson, E. N. <strong>KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy.</strong> J. Clin. Invest. 124: 3529-3539, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24960163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24960163</a>] [<a href="https://doi.org/10.1172/JCI74994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24960163">Garg et al. (2014)</a> found that Klhl40 -/- mice were indistinguishable from wildtype at birth, but they failed to grow, and none survived past 3 weeks of age. At 1 day of age, hindlimb skeletal muscle appeared normal, but it showed at least 50% less strength than wildtype. At 1 week of age, Klhl40 -/- skeletal muscle fibers appeared abnormal, with Z-line streaming, widened Z discs, and reduced content of Neb and Lmod3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24960163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span href="#mimAllelicVariantsFold" id="mimAllelicVariantsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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</span>
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<strong>5 Selected Examples</a>):</strong>
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</h4>
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<p />
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<div id="mimAllelicVariantsFold" class="collapse in mimTextToggleFold">
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<a href="/allelicVariants/615340" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=615340[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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<a id="0001" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0001 NEMALINE MYOPATHY 8</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<div style="float: left;">
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KLHL40, GLU528LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397509419 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509419;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs397509419?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397509419" 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=rs397509419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000054410 OR RCV001268125" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000054410, RCV001268125" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000054410...</a>
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<span class="mim-text-font">
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<p>In affected members of 2 consanguineous families of Turkish and Kurdish origin, respectively, with nemaline myopathy-8 (NEM8; <a href="/entry/615348">615348</a>), <a href="#3" class="mim-tip-reference" title="Ravenscroft, G., Miyatake, S., Lehtokari, V.-L., Todd, E. J., Vornanen, P., Yau, K. S., Hayashi, Y. K., Miyake, N., Tsurusaki, Y., Doi, H., Saitsu, H., Osaka, H., and 43 others. <strong>Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.</strong> Am. J. Hum. Genet. 93: 6-18, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23746549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23746549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23746549[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.2013.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23746549">Ravenscroft et al. (2013)</a> identified a homozygous c.1582G-A transition in exon 4 of the KLHL40 gene, resulting in a glu528-to-lys (E528K) substitution at a conserved residue in Kelch repeat domain-4. The mutation, which was identified by whole-exome sequencing and segregated with the disorder, was not found in several large control databases. Subsequent screening of this gene in a large cohort of patients with a similar phenotype identified the homozygous E528K mutation in another Kurdish family and in 9 Japanese families. The E528K mutation was found in 1 of 510 Japanese controls, yielding a frequency of 0.0098 in this population. The mutation was estimated to have arisen in the Japanese population about 4,900 years ago, consistent with a founder effect. However, haplotype analysis showed a different haplotype between a Japanese and Turkish family with the mutation, indicating that the mutation arose independently in these populations. Another Japanese family in whom exome sequencing was performed was found to be compound heterozygous for E528K and a c.1405G-T transversion in exon 3 of the KLHL40 gene, resulting in a gly469-to-cys (G469C; <a href="#0002">615340.0002</a>) substitution in Kelch repeat domain-3. Affected members of yet another Japanese family were homozygous for G469C. Structural modeling suggested that both mutations would destabilize hydrogen bonds and thus impair protein stability. Another Japanese and a Korean family were compound heterozygous for E528K and another pathogenic truncating mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23746549" 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 id="0002" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0002 NEMALINE MYOPATHY 8</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<div style="float: left;">
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KLHL40, GLY469CYS
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs367579275 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs367579275;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs367579275?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs367579275" 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=rs367579275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000054411" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000054411" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000054411</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the gly469-to-cys (G469C) mutation in the KLHL40 gene that was found in compound heterozygous state in patients with nemaline myopathy-8 (NEM8; <a href="/entry/615348">615348</a>) by <a href="#3" class="mim-tip-reference" title="Ravenscroft, G., Miyatake, S., Lehtokari, V.-L., Todd, E. J., Vornanen, P., Yau, K. S., Hayashi, Y. K., Miyake, N., Tsurusaki, Y., Doi, H., Saitsu, H., Osaka, H., and 43 others. <strong>Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.</strong> Am. J. Hum. Genet. 93: 6-18, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23746549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23746549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23746549[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.2013.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23746549">Ravenscroft et al. (2013)</a>, see <a href="#0001">615340.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23746549" 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 id="0003" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0003 NEMALINE MYOPATHY 8</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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<div style="float: left;">
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KLHL40, TRP201LEU
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397509420 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509420;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs397509420?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397509420" 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=rs397509420" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000054412" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000054412" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000054412</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a Turkish family with nemaline myopathy-8 (NEM8; <a href="/entry/615348">615348</a>), <a href="#3" class="mim-tip-reference" title="Ravenscroft, G., Miyatake, S., Lehtokari, V.-L., Todd, E. J., Vornanen, P., Yau, K. S., Hayashi, Y. K., Miyake, N., Tsurusaki, Y., Doi, H., Saitsu, H., Osaka, H., and 43 others. <strong>Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.</strong> Am. J. Hum. Genet. 93: 6-18, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23746549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23746549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23746549[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.2013.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23746549">Ravenscroft et al. (2013)</a> identified a homozygous c.602G-T transversion in exon 1 of the KLHL40 gene, resulting in a trp201-to-leu (W201L) substitution at a conserved residue in the BACK domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder and was not found in several large control databases. Structural modeling suggested that the mutation would destabilize hydrogen bonds and thus impair protein stability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23746549" 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 id="0004" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0004 NEMALINE MYOPATHY 8</strong>
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</span>
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</h4>
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KLHL40, ALA538PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397509421 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509421;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs397509421?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397509421" 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=rs397509421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000054413" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000054413" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000054413</a>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a consanguineous Turkish family with nemaline myopathy-8 (NEM8; <a href="/entry/615348">615348</a>), <a href="#3" class="mim-tip-reference" title="Ravenscroft, G., Miyatake, S., Lehtokari, V.-L., Todd, E. J., Vornanen, P., Yau, K. S., Hayashi, Y. K., Miyake, N., Tsurusaki, Y., Doi, H., Saitsu, H., Osaka, H., and 43 others. <strong>Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.</strong> Am. J. Hum. Genet. 93: 6-18, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23746549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23746549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23746549[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.2013.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23746549">Ravenscroft et al. (2013)</a> identified a homozygous c.1612G-C transversion in exon 5 of the KLHL40 gene, resulting in an ala538-to-pro (A538P) substitution at a conserved residue in Kelch repeat domain-4. Structural modeling suggested that the mutation would destabilize hydrogen bonds and thus impair protein stability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23746549" 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 id="0005" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0005 NEMALINE MYOPATHY 8</strong>
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KLHL40, TRP201TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397509420 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509420;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs397509420?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397509420" 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=rs397509420" 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=RCV000054414 OR RCV000598839 OR RCV004757124" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000054414, RCV000598839, RCV004757124" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000054414...</a>
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<p>In affected members of a Norwegian family with nemaline myopathy-8 (NEM8; <a href="/entry/615348">615348</a>), <a href="#3" class="mim-tip-reference" title="Ravenscroft, G., Miyatake, S., Lehtokari, V.-L., Todd, E. J., Vornanen, P., Yau, K. S., Hayashi, Y. K., Miyake, N., Tsurusaki, Y., Doi, H., Saitsu, H., Osaka, H., and 43 others. <strong>Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.</strong> Am. J. Hum. Genet. 93: 6-18, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23746549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23746549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23746549[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.2013.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23746549">Ravenscroft et al. (2013)</a> identified a homozygous c.602G-A transition in exon 1 of the KLHL40 gene, resulting in a trp201-to-ter (W201X) substitution in the BACK domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23746549" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="Garg2014" class="mim-anchor"></a>
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Garg, A., O'Rourke, J., Long, C., Doering, J., Ravenscroft, G., Bezprozvannaya, S., Nelson, B. R., Beetz, N., Li, L., Chen, S., Laing, N. G., Grange, R. W., Bassel-Duby, R., Olson, E. N.
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<strong>KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy.</strong>
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J. Clin. Invest. 124: 3529-3539, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24960163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24960163</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24960163" 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/JCI74994" target="_blank">Full Text</a>]
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Hartz, P. A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 7/25/2013.
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Ravenscroft, G., Miyatake, S., Lehtokari, V.-L., Todd, E. J., Vornanen, P., Yau, K. S., Hayashi, Y. K., Miyake, N., Tsurusaki, Y., Doi, H., Saitsu, H., Osaka, H., and 43 others.
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<strong>Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.</strong>
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Am. J. Hum. Genet. 93: 6-18, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23746549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23746549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23746549[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=23746549" 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.2013.05.004" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 03/07/2018
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Cassandra L. Kniffin - updated : 8/1/2013
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Creation Date:
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<span class="mim-text-font">
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Patricia A. Hartz : 7/25/2013
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mgross : 03/07/2018
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carol : 01/11/2018<br>mgross : 10/21/2015<br>mcolton : 6/26/2015<br>tpirozzi : 9/12/2013<br>carol : 8/2/2013<br>ckniffin : 8/1/2013<br>mgross : 7/25/2013
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<strong>*</strong> 615340
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KELCH-LIKE 40: KLHL40
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<em>Alternative titles; symbols</em>
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SARCOSYNAPSIN; SYRP<br />
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KELCH REPEAT- AND BTB/POZ DOMAIN-CONTAINING PROTEIN 5; KBTBD5
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: KLHL40</em></strong>
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Cytogenetic location: 3p22.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:42,685,537-42,692,544 </span>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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3p22.1
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Nemaline myopathy 8, autosomal recessive
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<span class="mim-font">
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615348
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Autosomal recessive
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Cloning and Expression</strong>
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<p>Ravenscroft et al. (2013) reported that the 621-amino acid KLHL40 protein has an N-terminal BTB/BACK domain and 5 C-terminal Kelch repeats predicted to form a beta-propeller structure. RT-PCR analysis of human tissues detected highest expression in adult skeletal muscle, with much lower expression in heart, and very weak expression in pancreas. No expression was detected in brain, placenta, lung, liver, and kidney. In human fetal tissues, KLHL40 was detected in striated muscle only. Western blot analysis of human skeletal muscle showed that KLHL40 was more abundant in fetal muscle than in postnatal muscle. Western blot analysis of mouse tissues detected Klhl40 in skeletal muscle only. Expression of Klhl40 increased with differentiation in cultured mouse C2C12 myoblasts. Immunohistochemical analysis of human fetal skeletal muscle localized KLHL40 to the A-band. </p><p>By Northern blot analysis of mouse tissues, Garg et al. (2014) detected high Klhl40 expression in skeletal muscle, lower expression in heart, and little to no expression in other tissues examined. Electroporation of flexor digitorum brevis of adult mice showed localization of fluorescence-tagged Klhl40 at both the I band and A band. </p>
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<strong>Gene Structure</strong>
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<p>Ravenscroft et al. (2013) determined that the KLHL40 gene contains 6 coding exons. </p>
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<strong>Mapping</strong>
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<p>Hartz (2013) mapped the KLHL40 gene to chromosome 3p22.1 based on an alignment of the KLHL40 sequence (GenBank AK056577) with the genomic sequence (GRCh37).</p>
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<strong>Gene Function</strong>
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<p>Garg et al. (2014) found that, rather than promote proteasome-mediated protein degradation like other BTB-BACK-Kelch family proteins, mouse Klhl40 stabilized skeletal muscle Neb (161650) and Lmod3 (616112). Yeast 2-hybrid analysis of a human skeletal muscle cDNA library, followed by coimmunoprecipitation analysis, showed that Klhl40 interacted directly with NEB and LMOD3. In transfected COS7 cells, coexpression of Klhl40 stabilized NEB and LMOD3 proteins comparably to a proteasome inhibitor. Klhl40 reduced polyubiquitination of lys48 of LMOD3, which specifically marks a protein for proteasome-mediated degradation. </p>
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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>By whole-exome sequencing, Ravenscroft et al. (2013) identified homozygous or compound heterozygous mutations (see, e.g., 615340.0001-615340.0003) in the KLHL40 gene in affected members from 6 families with autosomal recessive severe nemaline myopathy-8 (NEM8; 615348). The mutations segregated with the disorder and were not found in several large control databases. Subsequent screening of KLHL40 by Sanger sequencing in additional probands with severe NEM resulted in the identification of a total of 19 variants in 28 (19.6%) of 143 families affected by severe NEM. There were 4 frameshifts, 12 missense mutations, 2 nonsense mutations, and 1 splice site mutation, and the mutations were scattered throughout all exons. One mutation (E528K; 615340.0001) was identified to be a founder mutation among Japanese individuals. Structural analysis of the missense mutations indicated that they would most likely destabilize bonds or hydrophobic cores, resulting in protein instability. In addition, 129 probands with a milder phenotype were screened, but no KLHL40 mutations were identified in this cohort, confirming that KLHL40 mutations are most likely exclusive to severe cases. The phenotype was severe and included fetal akinesia or hypokinesia and contractures, fractures, respiratory failure, and swallowing difficulties apparent at birth. The average age at death was 5 months. Skeletal muscle biopsy showed absence of KLHL40 even in patients with 2 missense mutations, consistent with a loss of function mechanism, and up to 20% of patients had virtually no normal myofibrils ('miliary NEM'). Ravenscroft et al. (2013) suggested that the KLHL40 gene should be screened in individuals with autosomal recessive NEM who present with prenatal symptoms and/or contractures, as well as in all Japanese individuals with severe NEM. </p><p>By analyzing muscle samples from patients with nemalin myopathy and mutations in KLHL40, Garg et al. (2014) found that 2 patients with severe muscle pathology and complete deficiency of KLHL40 expression had marked reduction in LMOD3 and NEB. A third patient with less severe muscle pathology and residual KLHL40 had relatively normal LMOD3 and NEB content. </p>
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<strong>Animal Model</strong>
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<span class="mim-text-font">
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<p>The zebrafish genome contains 2 orthologs of KLHL40, Klhl40a and Klhl40b. RT-PCR detected Klhl40a prominently expressed in larval zebrafish and in adult heart and skeletal muscle, with much weaker expression in adult eye, skin, and brain. Klhl40b was prominently expressed in larval zebrafish and in adult skeletal muscle, with weaker expression in adult eye. Ravenscroft et al. (2013) found that morpholino-mediated knockdown of both Klhl40 genes in zebrafish resulted in a curved trunk and small head, with disrupted muscle patterning, gaps between myofibers, and widened Z-disks. Knockdown of either or both Klhl40 genes in zebrafish caused sporadic muscle tremors and absence of coordinated swimming. </p><p>Garg et al. (2014) found that Klhl40 -/- mice were indistinguishable from wildtype at birth, but they failed to grow, and none survived past 3 weeks of age. At 1 day of age, hindlimb skeletal muscle appeared normal, but it showed at least 50% less strength than wildtype. At 1 week of age, Klhl40 -/- skeletal muscle fibers appeared abnormal, with Z-line streaming, widened Z discs, and reduced content of Neb and Lmod3. </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>5 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 NEMALINE MYOPATHY 8</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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KLHL40, GLU528LYS
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<br />
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SNP: rs397509419,
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gnomAD: rs397509419,
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ClinVar: RCV000054410, RCV001268125
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of 2 consanguineous families of Turkish and Kurdish origin, respectively, with nemaline myopathy-8 (NEM8; 615348), Ravenscroft et al. (2013) identified a homozygous c.1582G-A transition in exon 4 of the KLHL40 gene, resulting in a glu528-to-lys (E528K) substitution at a conserved residue in Kelch repeat domain-4. The mutation, which was identified by whole-exome sequencing and segregated with the disorder, was not found in several large control databases. Subsequent screening of this gene in a large cohort of patients with a similar phenotype identified the homozygous E528K mutation in another Kurdish family and in 9 Japanese families. The E528K mutation was found in 1 of 510 Japanese controls, yielding a frequency of 0.0098 in this population. The mutation was estimated to have arisen in the Japanese population about 4,900 years ago, consistent with a founder effect. However, haplotype analysis showed a different haplotype between a Japanese and Turkish family with the mutation, indicating that the mutation arose independently in these populations. Another Japanese family in whom exome sequencing was performed was found to be compound heterozygous for E528K and a c.1405G-T transversion in exon 3 of the KLHL40 gene, resulting in a gly469-to-cys (G469C; 615340.0002) substitution in Kelch repeat domain-3. Affected members of yet another Japanese family were homozygous for G469C. Structural modeling suggested that both mutations would destabilize hydrogen bonds and thus impair protein stability. Another Japanese and a Korean family were compound heterozygous for E528K and another pathogenic truncating mutation. </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 NEMALINE MYOPATHY 8</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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KLHL40, GLY469CYS
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<br />
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SNP: rs367579275,
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gnomAD: rs367579275,
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ClinVar: RCV000054411
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the gly469-to-cys (G469C) mutation in the KLHL40 gene that was found in compound heterozygous state in patients with nemaline myopathy-8 (NEM8; 615348) by Ravenscroft et al. (2013), see 615340.0001. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 NEMALINE MYOPATHY 8</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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KLHL40, TRP201LEU
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<br />
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SNP: rs397509420,
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gnomAD: rs397509420,
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ClinVar: RCV000054412
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a Turkish family with nemaline myopathy-8 (NEM8; 615348), Ravenscroft et al. (2013) identified a homozygous c.602G-T transversion in exon 1 of the KLHL40 gene, resulting in a trp201-to-leu (W201L) substitution at a conserved residue in the BACK domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder and was not found in several large control databases. Structural modeling suggested that the mutation would destabilize hydrogen bonds and thus impair protein stability. </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 NEMALINE MYOPATHY 8</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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KLHL40, ALA538PRO
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<br />
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SNP: rs397509421,
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gnomAD: rs397509421,
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ClinVar: RCV000054413
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a consanguineous Turkish family with nemaline myopathy-8 (NEM8; 615348), Ravenscroft et al. (2013) identified a homozygous c.1612G-C transversion in exon 5 of the KLHL40 gene, resulting in an ala538-to-pro (A538P) substitution at a conserved residue in Kelch repeat domain-4. Structural modeling suggested that the mutation would destabilize hydrogen bonds and thus impair protein stability. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0005 NEMALINE MYOPATHY 8</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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KLHL40, TRP201TER
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<br />
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SNP: rs397509420,
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gnomAD: rs397509420,
|
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|
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ClinVar: RCV000054414, RCV000598839, RCV004757124
|
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</span>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of a Norwegian family with nemaline myopathy-8 (NEM8; 615348), Ravenscroft et al. (2013) identified a homozygous c.602G-A transition in exon 1 of the KLHL40 gene, resulting in a trp201-to-ter (W201X) substitution in the BACK domain. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</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">
|
|
Garg, A., O'Rourke, J., Long, C., Doering, J., Ravenscroft, G., Bezprozvannaya, S., Nelson, B. R., Beetz, N., Li, L., Chen, S., Laing, N. G., Grange, R. W., Bassel-Duby, R., Olson, E. N.
|
|
<strong>KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy.</strong>
|
|
J. Clin. Invest. 124: 3529-3539, 2014.
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|
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|
|
[PubMed: 24960163]
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|
|
[Full Text: https://doi.org/10.1172/JCI74994]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Hartz, P. A.
|
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<strong>Personal Communication.</strong>
|
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Baltimore, Md. 7/25/2013.
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|
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Ravenscroft, G., Miyatake, S., Lehtokari, V.-L., Todd, E. J., Vornanen, P., Yau, K. S., Hayashi, Y. K., Miyake, N., Tsurusaki, Y., Doi, H., Saitsu, H., Osaka, H., and 43 others.
|
|
<strong>Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.</strong>
|
|
Am. J. Hum. Genet. 93: 6-18, 2013.
|
|
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|
|
[PubMed: 23746549]
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|
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[Full Text: https://doi.org/10.1016/j.ajhg.2013.05.004]
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</p>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
|
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 03/07/2018<br>Cassandra L. Kniffin - updated : 8/1/2013
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</span>
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</div>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz : 7/25/2013
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</span>
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</div>
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</div>
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</div>
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<div>
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<br />
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</div>
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Edit History:
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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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mgross : 03/07/2018<br>carol : 01/11/2018<br>mgross : 10/21/2015<br>mcolton : 6/26/2015<br>tpirozzi : 9/12/2013<br>carol : 8/2/2013<br>ckniffin : 8/1/2013<br>mgross : 7/25/2013
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