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<title>
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Entry
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- *604407 - LEUCINE ZIPPER/EF-HAND-CONTAINING TRANSMEMBRANE PROTEIN 1; LETM1
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- OMIM
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<a href="/search/advanced/entry"> OMIM </a>
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<p>
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<span class="h4">*604407</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cytogenetics">Cytogenetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/604407">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000168924;t=ENST00000302787" 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=3954" 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=604407" 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=ENSG00000168924;t=ENST00000302787" 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_012318,XM_006713884,XM_047415673" 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_012318" 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=604407" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=05101&isoform_id=05101_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/LETM1" 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/4235226,6912482,15680275,18204589,57997058,62510844,119602966,119602967,194374295,578808155,2217350586,2462597107,2462597109,2462597111" 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/O95202" 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=3954" 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=ENSG00000168924;t=ENST00000302787" 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=LETM1" 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=LETM1" 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+3954" 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/LETM1" 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:3954" 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/3954" 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=chr4&hgg_gene=ENST00000302787.3&hgg_start=1811479&hgg_end=1856156&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:6556" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/letm1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=604407[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=604407[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000168924" 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=LETM1" 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=LETM1" 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=LETM1" 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=LETM1&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/PA30335" 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:6556" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0284252.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1932557" 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/LETM1#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:1932557" 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/3954/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=3954" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00010279;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-050522-154" 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=LETM1&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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604407
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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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LEUCINE ZIPPER/EF-HAND-CONTAINING TRANSMEMBRANE PROTEIN 1; LETM1
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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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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=LETM1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">LETM1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: <a href="/geneMap/4/35?start=-3&limit=10&highlight=35">4p16.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr4:1811479-1856156&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'})">4:1,811,479-1,856,156</a> </span>
|
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
|
</th>
|
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</tr>
|
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</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/4/35?start=-3&limit=10&highlight=35">
|
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4p16.3
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
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<a href="/entry/620089"> 620089 </a>
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<p>The LETM1 gene encodes an inner mitochondrial membrane protein with an osmoregulatory function that controls cation homeostasis. It functions as an electroneutral mitochondrial K+/H+ exchanger (KHE) and has also been linked to the regulation of Ca(2+) uptake or extrusion (summary by <a href="#4" class="mim-tip-reference" title="Kaiyrzhanov, R., Mohammed, S. E. M., Maroofian, R., Husain, R. A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Gronborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., and 42 others. <strong>Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.</strong> Am. J. Hum. Genet. 109: 1692-1712, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36055214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36055214</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36055214[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.2022.07.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36055214">Kaiyrzhanov et al., 2022</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36055214" 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="Endele, S., Fuhry, M., Pak, S. J., Zabel, B. U., Winterpacht, A. <strong>LETM1, a novel gene encoding a putative EF-hand Ca(2+)-binding protein, flanks the Wolf-Hirschhorn syndrome (WHS) critical region and is deleted in most WHS patients.</strong> Genomics 60: 218-225, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10486213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10486213</a>] [<a href="https://doi.org/10.1006/geno.1999.5881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10486213">Endele et al. (1999)</a> isolated LETM1 cDNA clones from human craniofacial, amniocyte, and normalized infant brain cDNA libraries. The deduced 739-amino acid protein is 83.8% identical to mouse Letm1 and contains 2 EF-hand calcium-binding sites, a transmembrane domain, a leucine zipper motif, several coiled-coil domains, and phosphorylation sites. Northern blot analysis showed that LETM1 was expressed in all adult and fetal human tissues tested. The authors identified 4 different transcript sizes, possibly resulting from alternative polyadenylation. RNA in situ hybridization showed that Letm1 expression was ubiquitous in mouse embryo sections at day 13.5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10486213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Schlickum, S., Moghekar, A., Simpson, J. C., Steglich, C., O'Brien, R. J., Winterpacht, A., Endele, S. U. <strong>LETM1, a gene deleted in Wolf-Hirschhorn syndrome, encodes an evolutionarily conserved mitochondrial protein.</strong> Genomics 83: 254-261, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14706454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14706454</a>] [<a href="https://doi.org/10.1016/j.ygeno.2003.08.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14706454">Schlickum et al. (2004)</a> determined that rat Letm1 localized to mitochondria of transfected human embryonic kidney cells. Deletion of an N-terminal domain containing a mitochondria targeting signal resulted in diffuse cytoplasmic staining. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14706454" 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 immunofluorescence and fractionation analyses in HeLa cells, <a href="#7" class="mim-tip-reference" title="Tamai, S., Iida, H., Yokota, S., Sayano, T., Kiguchiya, S., Ishihara, N., Hayashi, J., Mihara, K., Oka, T. <strong>Characterization of the mitochondrial protein LETM1, which maintains the mitochondrial tubular shapes and interacts with the AAA-ATPase BCS1L.</strong> J. Cell Sci. 121: 2588-2600, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18628306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18628306</a>] [<a href="https://doi.org/10.1242/jcs.026625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18628306">Tamai et al. (2008)</a> showed that LETM1 was a mitochondrial inner membrane protein. LTEM1 was synthesized as an 83-kD cytosolic precursor that was cleaved to generate the 70-kD mitochondrial protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18628306" 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 PCR using genomic DNA from PAC clones, <a href="#2" class="mim-tip-reference" title="Endele, S., Fuhry, M., Pak, S. J., Zabel, B. U., Winterpacht, A. <strong>LETM1, a novel gene encoding a putative EF-hand Ca(2+)-binding protein, flanks the Wolf-Hirschhorn syndrome (WHS) critical region and is deleted in most WHS patients.</strong> Genomics 60: 218-225, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10486213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10486213</a>] [<a href="https://doi.org/10.1006/geno.1999.5881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10486213">Endele et al. (1999)</a> determined the genomic structure of the LETM1 gene. The gene contains 14 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10486213" 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="Endele, S., Fuhry, M., Pak, S. J., Zabel, B. U., Winterpacht, A. <strong>LETM1, a novel gene encoding a putative EF-hand Ca(2+)-binding protein, flanks the Wolf-Hirschhorn syndrome (WHS) critical region and is deleted in most WHS patients.</strong> Genomics 60: 218-225, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10486213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10486213</a>] [<a href="https://doi.org/10.1006/geno.1999.5881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10486213">Endele et al. (1999)</a> mapped the LETM1 gene to chromosome 4p16.3 by FISH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10486213" 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="#1" class="mim-tip-reference" title="Dimmer, K. S., Navoni, F., Casarin, A., Trevisson, E., Endele, S., Winterpacht, A., Salviati, L., Scorrano, L. <strong>LETM1, deleted in Wolf-Hirschhorn syndrome is required for normal mitochondrial morphology and cellular viability.</strong> Hum. Molec. Genet. 17: 201-214, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17925330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17925330</a>] [<a href="https://doi.org/10.1093/hmg/ddm297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17925330">Dimmer et al. (2008)</a> found that human LETM1 localized to the inner mitochondrial membrane, was exposed to the matrix, and oligomerized into higher molecular mass complexes. Downregulation of LETM1 in HeLa cells via RNA interference did not disrupt these complexes, but it led to fragmentation of the mitochondrial network. Fragmentation was reversed by nigericin, which catalyzes the electroneutral exchange of K+ against H+. Downregulation of LETM1 caused necrosis-like death that was independent of caspase (see CASP1; <a href="/entry/147678">147678</a>) activation and refractory to BCL2 (<a href="/entry/151430">151430</a>) overexpression. Fibroblasts from Wolf-Hirschhorn syndrome (WHS; <a href="/entry/194190">194190</a>) patients, who are haploinsufficient for LETM1 due to monoallelic deletion of part of chromosome 4p, showed normal mitochondrial morphology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17925330" 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="#7" class="mim-tip-reference" title="Tamai, S., Iida, H., Yokota, S., Sayano, T., Kiguchiya, S., Ishihara, N., Hayashi, J., Mihara, K., Oka, T. <strong>Characterization of the mitochondrial protein LETM1, which maintains the mitochondrial tubular shapes and interacts with the AAA-ATPase BCS1L.</strong> J. Cell Sci. 121: 2588-2600, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18628306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18628306</a>] [<a href="https://doi.org/10.1242/jcs.026625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18628306">Tamai et al. (2008)</a> showed that LETM1 was crucial in the maintenance of mitochondrial tubular networks, as LETM1 knockdown in HeLa cells caused mitochondrial swelling. LETM1 was critical for formation of supercomplexes in the respiratory chains, including 3 different proton pumps. However, mitochondrial swelling was not caused by defects in assembly of the respiratory chains in LETM1-deficient cells. Further analysis demonstrated that LETM1 interacted specifically with BCS1L (<a href="/entry/603647">603647</a>) and that BCS1L stimulated assembly of the LETM1 complex. Like LETM1 knockdown, BCS1L downregulation caused disassembly of supercomplexes and abnormal mitochondrial morphology. However, the effects on the formation of individual complexes and mitochondrial morphology were different in BCS1L-knockdown cells than in LETM1-knockdown cells. The authors concluded that LETM1 and BCS1L have separate functions in different processes in the formation of tubular network structures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18628306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a genomewide Drosophila RNAi screen, <a href="#3" class="mim-tip-reference" title="Jiang, D., Zhao, L., Clapham, D. E. <strong>Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca(2+)/H(+) antiporter.</strong> Science 326: 144-147, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19797662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19797662</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19797662[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1175145" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19797662">Jiang et al. (2009)</a> identified Letm1 as a regulator of mitochondrial Ca(2+) and H+ concentrations. RNA knockdown, overexpression, and liposome reconstitution of purified Letm1 protein demonstrated that mammalian Letm1 is a mitochondrial Ca(2+)/H+ antiporter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19797662" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM; <a href="/entry/620089">620089</a>), <a href="#4" class="mim-tip-reference" title="Kaiyrzhanov, R., Mohammed, S. E. M., Maroofian, R., Husain, R. A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Gronborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., and 42 others. <strong>Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.</strong> Am. J. Hum. Genet. 109: 1692-1712, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36055214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36055214</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36055214[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.2022.07.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36055214">Kaiyrzhanov et al. (2022)</a> identified homozygous or compound heterozygous mutations in the LETM1 gene (see, e.g., <a href="#0001">604407.0001</a>-<a href="#0005">604407.0005</a>). The patients were ascertained through international collaboration and data sharing through the GeneMatcher Program after exome sequencing identified the mutations. There were 6 missense mutations, all within the conserved LETM domain, an in-frame deletion in the LETM domain, and 3 frameshift mutations affecting the C-terminal domain. Most of the variants were not present in the gnomAD database, although a few were present at a low frequency in only heterozygous state. Some, but not all, of the variants resulted in variably decreased LETM1 protein levels. <a href="#4" class="mim-tip-reference" title="Kaiyrzhanov, R., Mohammed, S. E. M., Maroofian, R., Husain, R. A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Gronborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., and 42 others. <strong>Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.</strong> Am. J. Hum. Genet. 109: 1692-1712, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36055214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36055214</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36055214[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.2022.07.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36055214">Kaiyrzhanov et al. (2022)</a> noted that previous studies had demonstrated that cellular LETM1 deficiency leads to uncompensated mitochondrial electrophoretic K+ uptake and loss of volume homeostasis, which causes mitochondrial fragmentation, matrix swelling, and disorganized cristae. Fibroblasts derived from a subset of their patients showed variable mitochondrial morphologic abnormalities, including increased fragmentation, irregular polarization patterns of mitochondrial network tubules, and shortened tubules. These abnormalities were associated with reduced inner membrane potential. Further studies of some patient fibroblasts and skeletal muscle samples showed variably decreased levels of OXPHOS complex proteins as well as cellular proliferation defects. Some of these mitochondrial defects could be rescued by using nigericin, a mitochondrial K+/H+ exchanger (KHE), illustrating the connection between mitochondrial dysfunction and impaired K+ homeostasis. Functional compensation studies in letm1-null yeast showed that the LETM1 mutations had variably impaired ability to rescue KHE activity, whereas wildtype could rescue KHE activity, thus demonstrating an adverse functional impact of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36055214" 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="Endele, S., Fuhry, M., Pak, S. J., Zabel, B. U., Winterpacht, A. <strong>LETM1, a novel gene encoding a putative EF-hand Ca(2+)-binding protein, flanks the Wolf-Hirschhorn syndrome (WHS) critical region and is deleted in most WHS patients.</strong> Genomics 60: 218-225, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10486213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10486213</a>] [<a href="https://doi.org/10.1006/geno.1999.5881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10486213">Endele et al. (1999)</a> reported that the LETM1 gene is deleted in nearly all Wolf-Hirschhorn syndrome patients and is located less than 80 kb distal to the minimal WHS critical region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10486213" 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>Wolf-Hirschhorn syndrome (WHS; <a href="/entry/194190">194190</a>) is a multigenic disorder resulting from a hemizygous deletion on chromosome 4. LETM1 is a candidate gene for seizures, a strong haploinsufficiency phenotype of WHS patients. <a href="#5" class="mim-tip-reference" title="McQuibban, A. G., Joza, N., Megighian, A., Scorzeto, M., Zanini, D., Reipert, S., Richter, C., Schweyen, R. J., Nowikovsky, K. <strong>A Drosophila mutant of LETM1, a candidate gene for seizures in Wolf-Hirschhorn syndrome.</strong> Hum. Molec. Genet. 19: 987-1000, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20026556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20026556</a>] [<a href="https://doi.org/10.1093/hmg/ddp563" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20026556">McQuibban et al. (2010)</a> identified the Drosophila gene CG4589 as the ortholog of LETM1 and renamed it DmLETM1. They assayed the effects of downregulating the DmLETM1 gene on mitochondrial function in vivo and in vitro. Conditional inactivation of DmLETM1 function in specific tissues resulted in roughening of the adult eye, mitochondrial swelling, and developmental lethality in third-instar larvae, possibly the result of deregulated mitophagy. Neuronal-specific downregulation of DmLETM1 resulted in impairment of locomotor behavior in the fly and reduced synaptic neurotransmitter release. DmLETM1 complemented growth and mitochondrial K+/H+ exchange (KHE) activity in yeast deficient for LETM1. The authors proposed that DmLETM1 functions as a mitochondrial osmoregulator through its mitochondrial K+/H+ exchange activity and may explain part of the pathophysiologic WHS phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20026556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 sibs, born of unrelated British parents (family 1), with childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM; <a href="/entry/620089">620089</a>), <a href="#4" class="mim-tip-reference" title="Kaiyrzhanov, R., Mohammed, S. E. M., Maroofian, R., Husain, R. A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Gronborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., and 42 others. <strong>Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.</strong> Am. J. Hum. Genet. 109: 1692-1712, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36055214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36055214</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36055214[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.2022.07.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36055214">Kaiyrzhanov et al. (2022)</a> identified compound heterozygous mutations in the LETM1 gene: a c.878T-A transversion (c.878T-A, NM_012318.3), resulting in an ile293-to-asn (I293N) substitution at a semi-conserved residue in the LETM domain, and a 1-bp deletion (c.2094del; <a href="#0002">604407.0002</a>), predicted to result in a frameshift and premature termination (Asp699MetfsTer13). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were each inherited from an affected parent, indicating familial segregation. Neither variant was present in the gnomAD database. Patient fibroblasts showed decreased levels of the LETM1 protein compared to controls. The mitochondria displayed morphologic abnormalities and reduced inner membrane potential, and there was a severe decrease in mitochondrial respiratory complexes I and IV. Ectopic expression of the variants in yeast marginally rescued mitochondrial KHE activity. The patients, who were 35 and 25 years of age, had a slowly progressive neurodegenerative disorder with spasticity, seizures, hearing loss, and visual impairment. Both developed diabetes mellitus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36055214" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>For discussion of the 1-bp deletion (c.2094del, NM_012318.3) in the LETM1 gene, predicted to result in a frameshift and premature termination (Asp699MetfsTer13), that was found in compound heterozygous state in 2 sibs with childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM; <a href="/entry/620089">620089</a>) by <a href="#4" class="mim-tip-reference" title="Kaiyrzhanov, R., Mohammed, S. E. M., Maroofian, R., Husain, R. A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Gronborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., and 42 others. <strong>Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.</strong> Am. J. Hum. Genet. 109: 1692-1712, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36055214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36055214</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36055214[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.2022.07.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36055214">Kaiyrzhanov et al. (2022)</a>, see <a href="#0001">604407.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36055214" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2108832865 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2108832865;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs2108832865" 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=rs2108832865" 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=RCV002221678 OR RCV002226782 OR RCV002294480" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002221678, RCV002226782, RCV002294480" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002221678...</a>
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<p>In 3 patients from 2 unrelated consanguineous Pakistani families (families 2 and 7) with childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM; <a href="/entry/620089">620089</a>), <a href="#4" class="mim-tip-reference" title="Kaiyrzhanov, R., Mohammed, S. E. M., Maroofian, R., Husain, R. A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Gronborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., and 42 others. <strong>Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.</strong> Am. J. Hum. Genet. 109: 1692-1712, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36055214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36055214</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36055214[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.2022.07.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36055214">Kaiyrzhanov et al. (2022)</a> identified a homozygous c.2220G-C transversion (c.2220G-C, NM_012318.3) in the LETM1 gene, resulting in an extension of the protein past the termination codon (Ter740TyrExt26). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. It was not present in the gnomAD database. Patient-derived fibroblasts showed swollen and fragmented mitochondria and barely detectable LETM1 levels. Ectopic expression in yeast displayed reduced LETM1 levels and poorly improved the KHE activity, indicating a functional deficit. The patients had a slowly progressive disease course with developmental regression, optic atrophy, spasticity, and seizures. They were 8, 15, and 24 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36055214" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 NEURODEGENERATION, CHILDHOOD-ONSET, WITH MULTISYSTEM INVOLVEMENT DUE TO MITOCHONDRIAL DYSFUNCTION</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs750286012 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs750286012;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/rs750286012?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=rs750286012" 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=rs750286012" 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=RCV002221680 OR RCV002294481" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002221680, RCV002294481" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002221680...</a>
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<p>In 2 unrelated patients, each born of consanguineous parents (family 4 of Egyptian origin and family 8 of Italian origin), with childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM; <a href="/entry/620089">620089</a>), <a href="#4" class="mim-tip-reference" title="Kaiyrzhanov, R., Mohammed, S. E. M., Maroofian, R., Husain, R. A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Gronborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., and 42 others. <strong>Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.</strong> Am. J. Hum. Genet. 109: 1692-1712, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36055214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36055214</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36055214[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.2022.07.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36055214">Kaiyrzhanov et al. (2022)</a> identified a homozygous c.881G-A transition (c.881G-A, NM_012318.3) in the LETM1 gene, resulting in an arg294-to-gln (R294Q) substitution in the LETM domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. It was present in only heterozygous state at a low frequency in the gnomAD database (v3.1.2). Ectopic expression of the variant in yeast was unable to restore mitochondrial KHE activity and impaired overall growth. The boy in family 4 died at age 8 years. He had hearing loss, impaired vision, developmental regression, cardiac ventricular hypertrophy, and episodic lactic acidosis. The woman in family 8 was 39 years old. She had developmental delay since infancy, optic atrophy, deafness, and cerebellar ataxia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36055214" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 NEURODEGENERATION, CHILDHOOD-ONSET, WITH MULTISYSTEM INVOLVEMENT DUE TO MITOCHONDRIAL DYSFUNCTION</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs753284434 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs753284434;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/rs753284434?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=rs753284434" 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=rs753284434" 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=RCV002221684 OR RCV002294482" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002221684, RCV002294482" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002221684...</a>
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<p>In 2 sibs, born of consanguineous Portuguese parents (family 10), with childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM; <a href="/entry/620089">620089</a>), <a href="#4" class="mim-tip-reference" title="Kaiyrzhanov, R., Mohammed, S. E. M., Maroofian, R., Husain, R. A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Gronborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., and 42 others. <strong>Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.</strong> Am. J. Hum. Genet. 109: 1692-1712, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36055214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36055214</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36055214[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.2022.07.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36055214">Kaiyrzhanov et al. (2022)</a> identified a homozygous C-to-G transversion (c.2071-9C-G, NM_012318.3) in intron 13 of the LETM1 gene, predicted to result in a frameshift and premature termination (Val691fsTer4). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Patient fibroblasts showed increased levels of LETM1 protein, suggesting that the variant likely escaped nonsense-mediated mRNA decay. However, in vitro studies showed that the mutant protein was nonfunctional. The patients carrying this mutation had a rapidly progressive disease course and died in the first months of life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36055214" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Dimmer2008" class="mim-anchor"></a>
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Dimmer, K. S., Navoni, F., Casarin, A., Trevisson, E., Endele, S., Winterpacht, A., Salviati, L., Scorrano, L.
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<strong>LETM1, deleted in Wolf-Hirschhorn syndrome is required for normal mitochondrial morphology and cellular viability.</strong>
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Hum. Molec. Genet. 17: 201-214, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17925330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17925330</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17925330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddm297" target="_blank">Full Text</a>]
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Endele, S., Fuhry, M., Pak, S. J., Zabel, B. U., Winterpacht, A.
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<strong>LETM1, a novel gene encoding a putative EF-hand Ca(2+)-binding protein, flanks the Wolf-Hirschhorn syndrome (WHS) critical region and is deleted in most WHS patients.</strong>
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Genomics 60: 218-225, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10486213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10486213</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10486213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1999.5881" target="_blank">Full Text</a>]
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<a id="Jiang2009" class="mim-anchor"></a>
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Jiang, D., Zhao, L., Clapham, D. E.
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<strong>Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca(2+)/H(+) antiporter.</strong>
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Science 326: 144-147, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19797662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19797662</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19797662[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=19797662" 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/10.1126/science.1175145" target="_blank">Full Text</a>]
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Kaiyrzhanov, R., Mohammed, S. E. M., Maroofian, R., Husain, R. A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Gronborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., and 42 others.
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<strong>Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.</strong>
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Am. J. Hum. Genet. 109: 1692-1712, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36055214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36055214</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36055214[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=36055214" 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.2022.07.007" target="_blank">Full Text</a>]
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McQuibban, A. G., Joza, N., Megighian, A., Scorzeto, M., Zanini, D., Reipert, S., Richter, C., Schweyen, R. J., Nowikovsky, K.
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<strong>A Drosophila mutant of LETM1, a candidate gene for seizures in Wolf-Hirschhorn syndrome.</strong>
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Hum. Molec. Genet. 19: 987-1000, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20026556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20026556</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20026556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp563" target="_blank">Full Text</a>]
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<a id="Schlickum2004" class="mim-anchor"></a>
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Schlickum, S., Moghekar, A., Simpson, J. C., Steglich, C., O'Brien, R. J., Winterpacht, A., Endele, S. U.
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<strong>LETM1, a gene deleted in Wolf-Hirschhorn syndrome, encodes an evolutionarily conserved mitochondrial protein.</strong>
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Genomics 83: 254-261, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14706454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14706454</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14706454" 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.ygeno.2003.08.013" target="_blank">Full Text</a>]
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<a id="Tamai2008" class="mim-anchor"></a>
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Tamai, S., Iida, H., Yokota, S., Sayano, T., Kiguchiya, S., Ishihara, N., Hayashi, J., Mihara, K., Oka, T.
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<strong>Characterization of the mitochondrial protein LETM1, which maintains the mitochondrial tubular shapes and interacts with the AAA-ATPase BCS1L.</strong>
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J. Cell Sci. 121: 2588-2600, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18628306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18628306</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18628306" 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/10.1242/jcs.026625" 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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Bao Lige - updated : 05/15/2023
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 10/20/2022<br>George E. Tiller - updated : 11/10/2011<br>Ada Hamosh - updated : 11/13/2009<br>Patricia A. Hartz - updated : 5/4/2009<br>Patricia A. Hartz - updated : 3/5/2004
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse : 1/5/2000
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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 : 05/15/2023
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carol : 10/26/2022<br>carol : 10/25/2022<br>ckniffin : 10/20/2022<br>alopez : 11/16/2011<br>terry : 11/10/2011<br>alopez : 11/16/2009<br>terry : 11/13/2009<br>mgross : 5/13/2009<br>mgross : 5/13/2009<br>terry : 5/4/2009<br>mgross : 3/9/2004<br>terry : 3/5/2004<br>carol : 1/6/2000<br>carol : 1/5/2000
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<span class="mim-font">
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<strong>*</strong> 604407
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<h3>
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LEUCINE ZIPPER/EF-HAND-CONTAINING TRANSMEMBRANE PROTEIN 1; LETM1
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: LETM1</em></strong>
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<strong>
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<em>
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Cytogenetic location: 4p16.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 4:1,811,479-1,856,156 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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4p16.3
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<span class="mim-font">
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Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction
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<td>
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<span class="mim-font">
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620089
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<span class="mim-font">
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Autosomal recessive
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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<span class="mim-text-font">
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<p>The LETM1 gene encodes an inner mitochondrial membrane protein with an osmoregulatory function that controls cation homeostasis. It functions as an electroneutral mitochondrial K+/H+ exchanger (KHE) and has also been linked to the regulation of Ca(2+) uptake or extrusion (summary by Kaiyrzhanov et al., 2022). </p>
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<strong>Cloning and Expression</strong>
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<span class="mim-text-font">
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<p>Endele et al. (1999) isolated LETM1 cDNA clones from human craniofacial, amniocyte, and normalized infant brain cDNA libraries. The deduced 739-amino acid protein is 83.8% identical to mouse Letm1 and contains 2 EF-hand calcium-binding sites, a transmembrane domain, a leucine zipper motif, several coiled-coil domains, and phosphorylation sites. Northern blot analysis showed that LETM1 was expressed in all adult and fetal human tissues tested. The authors identified 4 different transcript sizes, possibly resulting from alternative polyadenylation. RNA in situ hybridization showed that Letm1 expression was ubiquitous in mouse embryo sections at day 13.5. </p><p>Schlickum et al. (2004) determined that rat Letm1 localized to mitochondria of transfected human embryonic kidney cells. Deletion of an N-terminal domain containing a mitochondria targeting signal resulted in diffuse cytoplasmic staining. </p><p>By immunofluorescence and fractionation analyses in HeLa cells, Tamai et al. (2008) showed that LETM1 was a mitochondrial inner membrane protein. LTEM1 was synthesized as an 83-kD cytosolic precursor that was cleaved to generate the 70-kD mitochondrial protein. </p>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>By PCR using genomic DNA from PAC clones, Endele et al. (1999) determined the genomic structure of the LETM1 gene. The gene contains 14 exons. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Endele et al. (1999) mapped the LETM1 gene to chromosome 4p16.3 by FISH. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Dimmer et al. (2008) found that human LETM1 localized to the inner mitochondrial membrane, was exposed to the matrix, and oligomerized into higher molecular mass complexes. Downregulation of LETM1 in HeLa cells via RNA interference did not disrupt these complexes, but it led to fragmentation of the mitochondrial network. Fragmentation was reversed by nigericin, which catalyzes the electroneutral exchange of K+ against H+. Downregulation of LETM1 caused necrosis-like death that was independent of caspase (see CASP1; 147678) activation and refractory to BCL2 (151430) overexpression. Fibroblasts from Wolf-Hirschhorn syndrome (WHS; 194190) patients, who are haploinsufficient for LETM1 due to monoallelic deletion of part of chromosome 4p, showed normal mitochondrial morphology. </p><p>Tamai et al. (2008) showed that LETM1 was crucial in the maintenance of mitochondrial tubular networks, as LETM1 knockdown in HeLa cells caused mitochondrial swelling. LETM1 was critical for formation of supercomplexes in the respiratory chains, including 3 different proton pumps. However, mitochondrial swelling was not caused by defects in assembly of the respiratory chains in LETM1-deficient cells. Further analysis demonstrated that LETM1 interacted specifically with BCS1L (603647) and that BCS1L stimulated assembly of the LETM1 complex. Like LETM1 knockdown, BCS1L downregulation caused disassembly of supercomplexes and abnormal mitochondrial morphology. However, the effects on the formation of individual complexes and mitochondrial morphology were different in BCS1L-knockdown cells than in LETM1-knockdown cells. The authors concluded that LETM1 and BCS1L have separate functions in different processes in the formation of tubular network structures. </p><p>Using a genomewide Drosophila RNAi screen, Jiang et al. (2009) identified Letm1 as a regulator of mitochondrial Ca(2+) and H+ concentrations. RNA knockdown, overexpression, and liposome reconstitution of purified Letm1 protein demonstrated that mammalian Letm1 is a mitochondrial Ca(2+)/H+ antiporter. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM; 620089), Kaiyrzhanov et al. (2022) identified homozygous or compound heterozygous mutations in the LETM1 gene (see, e.g., 604407.0001-604407.0005). The patients were ascertained through international collaboration and data sharing through the GeneMatcher Program after exome sequencing identified the mutations. There were 6 missense mutations, all within the conserved LETM domain, an in-frame deletion in the LETM domain, and 3 frameshift mutations affecting the C-terminal domain. Most of the variants were not present in the gnomAD database, although a few were present at a low frequency in only heterozygous state. Some, but not all, of the variants resulted in variably decreased LETM1 protein levels. Kaiyrzhanov et al. (2022) noted that previous studies had demonstrated that cellular LETM1 deficiency leads to uncompensated mitochondrial electrophoretic K+ uptake and loss of volume homeostasis, which causes mitochondrial fragmentation, matrix swelling, and disorganized cristae. Fibroblasts derived from a subset of their patients showed variable mitochondrial morphologic abnormalities, including increased fragmentation, irregular polarization patterns of mitochondrial network tubules, and shortened tubules. These abnormalities were associated with reduced inner membrane potential. Further studies of some patient fibroblasts and skeletal muscle samples showed variably decreased levels of OXPHOS complex proteins as well as cellular proliferation defects. Some of these mitochondrial defects could be rescued by using nigericin, a mitochondrial K+/H+ exchanger (KHE), illustrating the connection between mitochondrial dysfunction and impaired K+ homeostasis. Functional compensation studies in letm1-null yeast showed that the LETM1 mutations had variably impaired ability to rescue KHE activity, whereas wildtype could rescue KHE activity, thus demonstrating an adverse functional impact of the mutations. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Endele et al. (1999) reported that the LETM1 gene is deleted in nearly all Wolf-Hirschhorn syndrome patients and is located less than 80 kb distal to the minimal WHS critical region. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Wolf-Hirschhorn syndrome (WHS; 194190) is a multigenic disorder resulting from a hemizygous deletion on chromosome 4. LETM1 is a candidate gene for seizures, a strong haploinsufficiency phenotype of WHS patients. McQuibban et al. (2010) identified the Drosophila gene CG4589 as the ortholog of LETM1 and renamed it DmLETM1. They assayed the effects of downregulating the DmLETM1 gene on mitochondrial function in vivo and in vitro. Conditional inactivation of DmLETM1 function in specific tissues resulted in roughening of the adult eye, mitochondrial swelling, and developmental lethality in third-instar larvae, possibly the result of deregulated mitophagy. Neuronal-specific downregulation of DmLETM1 resulted in impairment of locomotor behavior in the fly and reduced synaptic neurotransmitter release. DmLETM1 complemented growth and mitochondrial K+/H+ exchange (KHE) activity in yeast deficient for LETM1. The authors proposed that DmLETM1 functions as a mitochondrial osmoregulator through its mitochondrial K+/H+ exchange activity and may explain part of the pathophysiologic WHS phenotype. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>ALLELIC VARIANTS</strong>
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</span>
|
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<strong>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 NEURODEGENERATION, CHILDHOOD-ONSET, WITH MULTISYSTEM INVOLVEMENT DUE TO MITOCHONDRIAL DYSFUNCTION</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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LETM1, ILE293ASN
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<br />
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SNP: rs2108846420,
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ClinVar: RCV002221675, RCV002294478
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sibs, born of unrelated British parents (family 1), with childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM; 620089), Kaiyrzhanov et al. (2022) identified compound heterozygous mutations in the LETM1 gene: a c.878T-A transversion (c.878T-A, NM_012318.3), resulting in an ile293-to-asn (I293N) substitution at a semi-conserved residue in the LETM domain, and a 1-bp deletion (c.2094del; 604407.0002), predicted to result in a frameshift and premature termination (Asp699MetfsTer13). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were each inherited from an affected parent, indicating familial segregation. Neither variant was present in the gnomAD database. Patient fibroblasts showed decreased levels of the LETM1 protein compared to controls. The mitochondria displayed morphologic abnormalities and reduced inner membrane potential, and there was a severe decrease in mitochondrial respiratory complexes I and IV. Ectopic expression of the variants in yeast marginally rescued mitochondrial KHE activity. The patients, who were 35 and 25 years of age, had a slowly progressive neurodegenerative disorder with spasticity, seizures, hearing loss, and visual impairment. Both developed diabetes mellitus. </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 NEURODEGENERATION, CHILDHOOD-ONSET, WITH MULTISYSTEM INVOLVEMENT DUE TO MITOCHONDRIAL DYSFUNCTION</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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LETM1, 1-BP DEL, NT2094
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<br />
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SNP: rs2108832976,
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ClinVar: RCV002221677, RCV002294479
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</span>
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</div>
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<p>For discussion of the 1-bp deletion (c.2094del, NM_012318.3) in the LETM1 gene, predicted to result in a frameshift and premature termination (Asp699MetfsTer13), that was found in compound heterozygous state in 2 sibs with childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM; 620089) by Kaiyrzhanov et al. (2022), see 604407.0001. </p>
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<strong>.0003 NEURODEGENERATION, CHILDHOOD-ONSET, WITH MULTISYSTEM INVOLVEMENT DUE TO MITOCHONDRIAL DYSFUNCTION</strong>
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LETM1, c.2220G-C
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<br />
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SNP: rs2108832865,
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ClinVar: RCV002221678, RCV002226782, RCV002294480
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<p>In 3 patients from 2 unrelated consanguineous Pakistani families (families 2 and 7) with childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM; 620089), Kaiyrzhanov et al. (2022) identified a homozygous c.2220G-C transversion (c.2220G-C, NM_012318.3) in the LETM1 gene, resulting in an extension of the protein past the termination codon (Ter740TyrExt26). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. It was not present in the gnomAD database. Patient-derived fibroblasts showed swollen and fragmented mitochondria and barely detectable LETM1 levels. Ectopic expression in yeast displayed reduced LETM1 levels and poorly improved the KHE activity, indicating a functional deficit. The patients had a slowly progressive disease course with developmental regression, optic atrophy, spasticity, and seizures. They were 8, 15, and 24 years of age. </p>
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<h4>
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<span class="mim-font">
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<strong>.0004 NEURODEGENERATION, CHILDHOOD-ONSET, WITH MULTISYSTEM INVOLVEMENT DUE TO MITOCHONDRIAL DYSFUNCTION</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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LETM1, ARG294GLN
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<br />
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SNP: rs750286012,
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gnomAD: rs750286012,
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ClinVar: RCV002221680, RCV002294481
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<p>In 2 unrelated patients, each born of consanguineous parents (family 4 of Egyptian origin and family 8 of Italian origin), with childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM; 620089), Kaiyrzhanov et al. (2022) identified a homozygous c.881G-A transition (c.881G-A, NM_012318.3) in the LETM1 gene, resulting in an arg294-to-gln (R294Q) substitution in the LETM domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. It was present in only heterozygous state at a low frequency in the gnomAD database (v3.1.2). Ectopic expression of the variant in yeast was unable to restore mitochondrial KHE activity and impaired overall growth. The boy in family 4 died at age 8 years. He had hearing loss, impaired vision, developmental regression, cardiac ventricular hypertrophy, and episodic lactic acidosis. The woman in family 8 was 39 years old. She had developmental delay since infancy, optic atrophy, deafness, and cerebellar ataxia. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 NEURODEGENERATION, CHILDHOOD-ONSET, WITH MULTISYSTEM INVOLVEMENT DUE TO MITOCHONDRIAL DYSFUNCTION</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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LETM1, IVS13AS, C-G, -9
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<br />
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SNP: rs753284434,
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gnomAD: rs753284434,
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ClinVar: RCV002221684, RCV002294482
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sibs, born of consanguineous Portuguese parents (family 10), with childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM; 620089), Kaiyrzhanov et al. (2022) identified a homozygous C-to-G transversion (c.2071-9C-G, NM_012318.3) in intron 13 of the LETM1 gene, predicted to result in a frameshift and premature termination (Val691fsTer4). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Patient fibroblasts showed increased levels of LETM1 protein, suggesting that the variant likely escaped nonsense-mediated mRNA decay. However, in vitro studies showed that the mutant protein was nonfunctional. The patients carrying this mutation had a rapidly progressive disease course and died in the first months of life. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<ol>
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<li>
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Dimmer, K. S., Navoni, F., Casarin, A., Trevisson, E., Endele, S., Winterpacht, A., Salviati, L., Scorrano, L.
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<strong>LETM1, deleted in Wolf-Hirschhorn syndrome is required for normal mitochondrial morphology and cellular viability.</strong>
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Hum. Molec. Genet. 17: 201-214, 2008.
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[PubMed: 17925330]
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[Full Text: https://doi.org/10.1093/hmg/ddm297]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Endele, S., Fuhry, M., Pak, S. J., Zabel, B. U., Winterpacht, A.
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<strong>LETM1, a novel gene encoding a putative EF-hand Ca(2+)-binding protein, flanks the Wolf-Hirschhorn syndrome (WHS) critical region and is deleted in most WHS patients.</strong>
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Genomics 60: 218-225, 1999.
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[PubMed: 10486213]
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[Full Text: https://doi.org/10.1006/geno.1999.5881]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Jiang, D., Zhao, L., Clapham, D. E.
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<strong>Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca(2+)/H(+) antiporter.</strong>
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Science 326: 144-147, 2009.
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[PubMed: 19797662]
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[Full Text: https://doi.org/10.1126/science.1175145]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kaiyrzhanov, R., Mohammed, S. E. M., Maroofian, R., Husain, R. A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Gronborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., and 42 others.
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<strong>Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.</strong>
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Am. J. Hum. Genet. 109: 1692-1712, 2022.
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[PubMed: 36055214]
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[Full Text: https://doi.org/10.1016/j.ajhg.2022.07.007]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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McQuibban, A. G., Joza, N., Megighian, A., Scorzeto, M., Zanini, D., Reipert, S., Richter, C., Schweyen, R. J., Nowikovsky, K.
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<strong>A Drosophila mutant of LETM1, a candidate gene for seizures in Wolf-Hirschhorn syndrome.</strong>
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Hum. Molec. Genet. 19: 987-1000, 2010.
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[PubMed: 20026556]
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[Full Text: https://doi.org/10.1093/hmg/ddp563]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Schlickum, S., Moghekar, A., Simpson, J. C., Steglich, C., O'Brien, R. J., Winterpacht, A., Endele, S. U.
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<strong>LETM1, a gene deleted in Wolf-Hirschhorn syndrome, encodes an evolutionarily conserved mitochondrial protein.</strong>
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Genomics 83: 254-261, 2004.
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[PubMed: 14706454]
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[Full Text: https://doi.org/10.1016/j.ygeno.2003.08.013]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Tamai, S., Iida, H., Yokota, S., Sayano, T., Kiguchiya, S., Ishihara, N., Hayashi, J., Mihara, K., Oka, T.
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<strong>Characterization of the mitochondrial protein LETM1, which maintains the mitochondrial tubular shapes and interacts with the AAA-ATPase BCS1L.</strong>
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J. Cell Sci. 121: 2588-2600, 2008.
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[PubMed: 18628306]
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[Full Text: https://doi.org/10.1242/jcs.026625]
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</p>
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</li>
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</ol>
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<br />
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Contributors:
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Bao Lige - updated : 05/15/2023<br>Cassandra L. Kniffin - updated : 10/20/2022<br>George E. Tiller - updated : 11/10/2011<br>Ada Hamosh - updated : 11/13/2009<br>Patricia A. Hartz - updated : 5/4/2009<br>Patricia A. Hartz - updated : 3/5/2004
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Paul J. Converse : 1/5/2000
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mgross : 05/15/2023<br>carol : 10/26/2022<br>carol : 10/25/2022<br>ckniffin : 10/20/2022<br>alopez : 11/16/2011<br>terry : 11/10/2011<br>alopez : 11/16/2009<br>terry : 11/13/2009<br>mgross : 5/13/2009<br>mgross : 5/13/2009<br>terry : 5/4/2009<br>mgross : 3/9/2004<br>terry : 3/5/2004<br>carol : 1/6/2000<br>carol : 1/5/2000
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