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<title>
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Entry
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- *300169 - APOPTOSIS-INDUCING FACTOR, MITOCHONDRIA-ASSOCIATED, 1; AIFM1
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- OMIM
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</nav>
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="row">
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<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
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<div class="form-group">
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<div class="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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</li>
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<li role="separator" class="divider"></li>
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<li>
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<a href="/history"> Search History </a>
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</ul>
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<div class="autocomplete" id="mimEntrySearchAutocomplete"></div>
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<span class="small">
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</span>
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</div>
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</form>
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<div class="row">
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<p />
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</div>
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</div>
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</div>
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<div id="mimContent">
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<div class="container hidden-print">
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<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
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<div id="mimAlertBanner">
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</div>
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</div>
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</div>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*300169</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/300169">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=ENSG00000156709;t=ENST00000287295" 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=9131" 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=300169" 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=ENSG00000156709;t=ENST00000287295" 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_001130846,NM_001130847,NM_004208,NM_145812,NR_132647" 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_004208" 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=300169" 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=02161&isoform_id=02161_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/AIFM1" 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/4323587,4406579,4678807,4678809,4757732,13431764,22202629,48146875,55585892,55585894,68005569,68005602,68005633,83405866,119632215,119632216,119632217,141797018,189069389,195927006,332367901,444738069,923424571" 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/O95831" 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=9131" 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=ENSG00000156709;t=ENST00000287295" 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=AIFM1" 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=AIFM1" 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+9131" 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/AIFM1" 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:9131" 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/9131" 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=chrX&hgg_gene=ENST00000287295.8&hgg_start=130129362&hgg_end=130165841&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:8768" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=300169[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=300169[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/AIFM1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000156709" 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=AIFM1" 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=AIFM1" 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=AIFM1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/AIFM1" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=AIFM1&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/PA162376129" 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:8768" 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/FBgn0031392.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:1349419" 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/AIFM1#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:1349419" 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/9131/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=9131" 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=WBGene00006937;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-030826-11" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:9131" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=AIFM1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 763400005<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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300169
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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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APOPTOSIS-INDUCING FACTOR, MITOCHONDRIA-ASSOCIATED, 1; AIFM1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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APOPTOSIS-INDUCING FACTOR; AIF<br />
|
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PROGRAMMED CELL DEATH 8; PDCD8
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=AIFM1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">AIFM1</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/X/675?start=-3&limit=10&highlight=675">Xq26.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:130129362-130165841&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'})">X:130,129,362-130,165,841</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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Combined oxidative phosphorylation deficiency 6
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Deafness, X-linked 5
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Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy
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<li><a href="/graph/linear/300169" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/300169" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>Description</strong>
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<p>The AIFM1 gene encodes a mitochondrial flavin adenine dinucleotide (FAD)-dependent oxidoreductase that plays a role in oxidative phosphorylation (OxPhos) and redox control in healthy cells. After mitochondrial outer membrane permeabilization, which is a feature of most, if not all, apoptotic pathways, AIFM1 is released from mitochondria and translocates to the nucleus, where it mediates nuclear features of apoptosis such as chromatin condensation and large-scale DNA degradation (summary by <a href="#12" class="mim-tip-reference" title="Joza, N., Pospisilik, J. A., Hangen, E., Hanada, T., Modjtahedi, N., Penninger, J. M., Kroemer, G. <strong>AIF: not just an apoptosis-inducing factor.</strong> Ann. N.Y. Acad. Sci. 1171: 2-11, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19723031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19723031</a>] [<a href="https://doi.org/10.1111/j.1749-6632.2009.04681.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19723031">Joza et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19723031" 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="#22" class="mim-tip-reference" title="Susin, S. A., Lorenzo, H. K., Zamzami, N., Marzo, I., Snow, B. E., Brothers, G. M., Mangion, J., Jacotot, E., Constantini, P., Loeffler, M., Larochette, N., Goodlett, D. R., Aebersold, R., Siderovski, D. P., Penninger, J. M., Kroemer, G. <strong>Molecular characterization of mitochondrial apoptosis-inducing factor.</strong> Nature 397: 441-446, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9989411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9989411</a>] [<a href="https://doi.org/10.1038/17135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9989411">Susin et al. (1999)</a> identified and cloned an apoptosis-inducing factor, AIF, that is sufficient to induce apoptosis of isolated nuclei. They cloned the mouse homolog of AIF, which has 92% amino acid identity to the human protein. The full-length proteins of both mouse and human contain 2 mitochondrial localization sequences and 2 putative nuclear localization signals. Mature mouse AIF has a molecular mass 57 kD that shares homology with the bacterial oxidoreductases, whereas the mouse precursor AIF transcript is 67 kD. AIF was normally confined to the mitochondrial intermembrane space, but translocated to the nucleus when apoptosis is induced. Recombinant AIF caused chromatin condensation and large scale fragmentation of DNA in isolated HeLa cell nuclei. It induced purified mitochondria to release the apoptogenic proteins cytochrome c (<a href="/entry/123970">123970</a>) and caspase-9 (<a href="/entry/602234">602234</a>). Microinjection of AIF into the cytoplasm of intact cells induced condensation of chromatin, dissipation of the mitochondrial transmembrane potential, and exposure of phosphatidylserine in the plasma membrane. None of the effects were prevented by pretreatment with a caspase inhibitor. Overexpression of BCL2 (<a href="/entry/151430">151430</a>), which controls the opening of mitochondrial permeability transition pores, prevented the release of AIF from the mitochondrion, but did not affect its apoptogenic activity. <a href="#22" class="mim-tip-reference" title="Susin, S. A., Lorenzo, H. K., Zamzami, N., Marzo, I., Snow, B. E., Brothers, G. M., Mangion, J., Jacotot, E., Constantini, P., Loeffler, M., Larochette, N., Goodlett, D. R., Aebersold, R., Siderovski, D. P., Penninger, J. M., Kroemer, G. <strong>Molecular characterization of mitochondrial apoptosis-inducing factor.</strong> Nature 397: 441-446, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9989411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9989411</a>] [<a href="https://doi.org/10.1038/17135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9989411">Susin et al. (1999)</a> concluded that AIF is the principal mitochondrial factor causing nuclear apoptosis. They postulated that the caspases, DFF/CAD (<a href="/entry/601883">601883</a>), and AIF are engaged in complementary cooperative or redundant pathways that lead to nuclear apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9989411" 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="#9" class="mim-tip-reference" title="Ghezzi, D., Sevrioukova, I., Invernizzi, F., Lamperti, C., Mora, M., D'Adamo, P., Novara, F., Zuffardi, O., Uziel, G., Zeviani, M. <strong>Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor.</strong> Am. J. Hum. Genet. 86: 639-649, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20362274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20362274</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20362274[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.2010.03.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20362274">Ghezzi et al. (2010)</a> identified human AIF as a 62-kD mature mitochondrion-specific protein that binds FAD and attaches by an N-terminal transmembrane domain to the inner mitochondrial membrane, where is functions as an NADH oxidase. Upon apoptogenic stimuli, the 57-kD soluble AIF containing 512 amino acids is released by proteolytic cleavage and translocates from the mitochondria to the nucleus, where it binds to chromosomal DNA and induces chromatin condensation and DNA fragmentation by attracting and activating a set of endonucleases. The full-length human precursor protein is a 67-kD polypeptide and contains 613 amino acids. After mitochondrial import, cleavage of a 54-amino acid mitochondrial targeting sequence results in the 62-kD mature protein containing 559 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20362274" 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="#27" class="mim-tip-reference" title="Zong, L., Guan, J., Ealy, M., Zhang, Q., Wang, D., Wang. H., Zhao, Y., Shen, Z., Campbell, C. A., Wang, F., Yang, J., Sun, W., and 18 others. <strong>Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder.</strong> J. Med. Genet. 52: 523-531, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25986071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25986071</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25986071[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/10.1136/jmedgenet-2014-102961" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25986071">Zong et al. (2015)</a> found ubiquitous expression of the Aifm1 gene in the mouse inner ear, especially in the cytoplasm of inner and outer hair cells and spiral ganglion neurons, consistent with a role in normal auditory function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25986071" 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>Mapping</strong>
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<p>By its inclusion within a mapped clone (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=Z81364" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">Z81364</a>), <a href="#22" class="mim-tip-reference" title="Susin, S. A., Lorenzo, H. K., Zamzami, N., Marzo, I., Snow, B. E., Brothers, G. M., Mangion, J., Jacotot, E., Constantini, P., Loeffler, M., Larochette, N., Goodlett, D. R., Aebersold, R., Siderovski, D. P., Penninger, J. M., Kroemer, G. <strong>Molecular characterization of mitochondrial apoptosis-inducing factor.</strong> Nature 397: 441-446, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9989411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9989411</a>] [<a href="https://doi.org/10.1038/17135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9989411">Susin et al. (1999)</a> mapped the AIFM1 gene to chromosome Xq25-q26. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9989411" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 1/30/2013."None>Gross (2013)</a> mapped the AIFM1 gene to chromosome Xq26.1 based on an alignment of the AIFM1 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AF100928" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AF100928</a>) with the genomic sequence (GRCh37).</p>
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<p>Programmed cell death is a fundamental requirement for embryogenesis, organ metamorphosis, and tissue homeostasis. In mammals, release of mitochondrial cytochrome c leads to cytosolic assembly of the apoptosome--a caspase activation complex involving APAF1 (<a href="/entry/602233">602233</a>) and caspase-9 that induces hallmarks of apoptosis. There are, however, mitochondrially regulated cell death pathways that are independent of APAF1/caspase-9. Like cytochrome c, AIF is localized to mitochondria and released in response to death stimuli. <a href="#13" class="mim-tip-reference" title="Joza, N., Susin, S. A., Daugas, E., Stanford, W. L., Cho, S. K., Li, C. Y. J., Sasaki, T., Elia, A. J., Cheng, H.-Y. M., Ravagnan, L., Ferri, K. F., Zamzami, N., Wakeham, A., Hakem, R., Yoshida, H., Kong, Y.-Y., Mak, T. W., Zuniga-Pflucker, J. C., Kroemer, G., Penninger, J. M. <strong>Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death.</strong> Nature 410: 549-554, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11279485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11279485</a>] [<a href="https://doi.org/10.1038/35069004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11279485">Joza et al. (2001)</a> showed that genetic inactivation of AIF renders embryonic stem cells resistant to cell death after serum deprivation. Moreover, AIF is essential for programmed cell death during cavitation of embryoid bodies--the very first wave of cell death indispensable for mouse morphogenesis. AIF-dependent cell death displays structural features of apoptosis, and can be genetically uncoupled from APAF1 and caspase-9 expression. <a href="#13" class="mim-tip-reference" title="Joza, N., Susin, S. A., Daugas, E., Stanford, W. L., Cho, S. K., Li, C. Y. J., Sasaki, T., Elia, A. J., Cheng, H.-Y. M., Ravagnan, L., Ferri, K. F., Zamzami, N., Wakeham, A., Hakem, R., Yoshida, H., Kong, Y.-Y., Mak, T. W., Zuniga-Pflucker, J. C., Kroemer, G., Penninger, J. M. <strong>Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death.</strong> Nature 410: 549-554, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11279485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11279485</a>] [<a href="https://doi.org/10.1038/35069004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11279485">Joza et al. (2001)</a> concluded that their data provide genetic evidence for a caspase-independent pathway of programmed cell death that controls early morphogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11279485" 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="#26" class="mim-tip-reference" title="Yu, S.-W., Wang, H., Poitras, M. F., Coombs, C., Bowers, W. J., Federoff, H. J., Poirier, G. G., Dawson, T. M., Dawson, V. L. <strong>Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor.</strong> Science 297: 259-263, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12114629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12114629</a>] [<a href="https://doi.org/10.1126/science.1072221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12114629">Yu et al. (2002)</a> demonstrated that poly(ADP-ribose) polymerase-1 (PARP1; <a href="/entry/173870">173870</a>) activation is required for translocation of AIF from the mitochondria to the nucleus and that AIF is necessary for PARP1-dependent cell death. N-methyl-N-prime-nitro-N-nitrosoguanidine, hydrogen peroxide, and NMDA induce AIF translocation and cell death, which is prevented by PARP inhibitors or genetic knockout of PARP1, but is caspase independent. Microinjection of an antibody to AIF protects against PARP1-dependent cytotoxicity. <a href="#26" class="mim-tip-reference" title="Yu, S.-W., Wang, H., Poitras, M. F., Coombs, C., Bowers, W. J., Federoff, H. J., Poirier, G. G., Dawson, T. M., Dawson, V. L. <strong>Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor.</strong> Science 297: 259-263, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12114629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12114629</a>] [<a href="https://doi.org/10.1126/science.1072221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12114629">Yu et al. (2002)</a> concluded that their data support a model in which PARP1 activation signals AIF release from mitochondria, resulting in a caspase-independent pathway of programmed cell death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12114629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Andrabi, S. A., Kim, N. S., Yu, S.-W., Wang, H., Koh, D. W., Sasaki, M., Klaus, J. A., Otsuka, T., Zhang, Z., Koehler, R. C., Hurn, P. D., Poirier, G. G., Dawson, V. L., Dawson, T. M. <strong>Poly(ADP-ribose) (PAR) polymer is a death signal.</strong> Proc. Nat. Acad. Sci. 103: 18308-18313, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17116882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17116882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17116882[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/10.1073/pnas.0606526103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17116882">Andrabi et al. (2006)</a> and <a href="#25" class="mim-tip-reference" title="Yu, S.-W., Andrabi, S. A., Wang, H., Kim, N. S., Poirier, G. G., Dawson, T. M., Dawson, V. L. <strong>Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death.</strong> Proc. Nat. Acad. Sci. 103: 18314-18319, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17116881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17116881</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17116881[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/10.1073/pnas.0606528103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17116881">Yu et al. (2006)</a> demonstrated that the product of PARP1 activity, poly(ADP-ribose) (PAR) polymer, mediates PARP1-induced cell death. <a href="#25" class="mim-tip-reference" title="Yu, S.-W., Andrabi, S. A., Wang, H., Kim, N. S., Poirier, G. G., Dawson, T. M., Dawson, V. L. <strong>Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death.</strong> Proc. Nat. Acad. Sci. 103: 18314-18319, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17116881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17116881</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17116881[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/10.1073/pnas.0606528103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17116881">Yu et al. (2006)</a> showed that PAR polymer induced the release of Aif from mitochondria in mouse cortical neurons and induced its translocation to nuclei. They also showed that poly(ADP-ribose) glycohydrolase (PARG; <a href="/entry/603501">603501</a>) prevented Parp1-dependent Aif release. Furthermore, cells with reduced levels of Aif were resistant to PARP1-dependent cell death and PAR polymer cytotoxicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17116882+17116881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Joza, N., Pospisilik, J. A., Hangen, E., Hanada, T., Modjtahedi, N., Penninger, J. M., Kroemer, G. <strong>AIF: not just an apoptosis-inducing factor.</strong> Ann. N.Y. Acad. Sci. 1171: 2-11, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19723031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19723031</a>] [<a href="https://doi.org/10.1111/j.1749-6632.2009.04681.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19723031">Joza et al. (2009)</a> provided a review of AIFM1 functional and animal model studies and discussed its role in caspase-independent cell death pathways, mitochondrial metabolism and redox control, and obesity and diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19723031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Combined Oxidative Phosphorylation Deficiency 6</em></strong></p><p>
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In 2 Italian male first cousins, born of monozygotic twin sisters and unrelated fathers, with combined oxidative phosphorylation deficiency resulting in a severe mitochondrial encephalomyopathy (COXPD6; <a href="/entry/300816">300816</a>), <a href="#9" class="mim-tip-reference" title="Ghezzi, D., Sevrioukova, I., Invernizzi, F., Lamperti, C., Mora, M., D'Adamo, P., Novara, F., Zuffardi, O., Uziel, G., Zeviani, M. <strong>Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor.</strong> Am. J. Hum. Genet. 86: 639-649, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20362274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20362274</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20362274[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.2010.03.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20362274">Ghezzi et al. (2010)</a> identified a hemizygous deletion in the AIFM1 gene (<a href="#0001">300169.0001</a>). Both had onset in the first year of life of psychomotor regression, muscle weakness and atrophy, lack of further development, and abnormal signals in the basal ganglia. One died at age 16 months, and the other was tetraplegic and wheelchair-bound with an inability to communicate at age 5 years. In vitro studies showed that the AIFM1 mutation resulted in destabilization of the inner mitochondrial membrane with subsequent damage to respiratory chain structure and activities. In addition, the mutation resulted in impaired control of mitochondrion-derived programmed cell death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20362274" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 brothers with COXPD6, <a href="#3" class="mim-tip-reference" title="Berger, I., Ben-Neriah, Z., Dor-Wolman, T., Shaag, A., Saada, A., Zenvirt, S., Raas-Rothschild, A., Nadjari, M., Kaestner, K. H., Elpeleg, O. <strong>Early prenatal ventriculomegaly due to an AIFM1 mutation identified by linkage analysis and whole exome sequencing.</strong> Molec. Genet. Metab. 104: 517-520, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22019070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22019070</a>] [<a href="https://doi.org/10.1016/j.ymgme.2011.09.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22019070">Berger et al. (2011)</a> identified a hemizygous mutation in the AIFM1 gene (G308E; <a href="#0012">300169.0012</a>). The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family; the unaffected mother was a carrier. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22019070" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 male first cousins, born of Italian sisters, with COXPD6, <a href="#8" class="mim-tip-reference" title="Diodato, D., Tasca, G., Verrigni, D., D'Amico, A., Rizza, T., Tozzi, G., Martinelli, D., Verardo, M., Invernizzi, F., Nasca, A., Bellachio, E., Ghezzi, D., Piemonte, F., Dionisi-Vici, C., Carrozzo, R., Bertini, E. <strong>A novel AIFM1 mutation expands the phenotype to an infantile motor neuron disease.</strong> Europ. J. Hum. Genet. 24: 463-466, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26173962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26173962</a>] [<a href="https://doi.org/10.1038/ejhg.2015.141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26173962">Diodato et al. (2016)</a> identified a hemizygous missense mutation in the AIFM1 gene (G338E; <a href="#0013">300169.0013</a>). The mutation, which was found by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP (build 142) or ExAC databases. Western blot analysis of patient cells showed decreased levels of the AIFM1 protein compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26173962" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Cowchock Syndrome/X-Linked Charcot-Marie-Tooth Disease 4 With or Without Cerebellar Ataxia</em></strong></p><p>
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In affected members of the original family with Cowchock syndrome (<a href="/entry/310490">310490</a>), also known as X-linked recessive Charcot-Marie-Tooth disease-4 (CMTX4), reported by <a href="#7" class="mim-tip-reference" title="Cowchock, F. S., Duckett, S. W., Streletz, L. J., Graziani, L. J., Jackson, L. G. <strong>X-linked motor-sensory neuropathy type-II with deafness and mental retardation: a new disorder.</strong> Am. J. Med. Genet. 20: 307-315, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3856385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3856385</a>] [<a href="https://doi.org/10.1002/ajmg.1320200214" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3856385">Cowchock et al. (1985)</a>, <a href="#20" class="mim-tip-reference" title="Rinaldi, C., Grunseich, C., Sevrioukova, I. F., Schindler, A., Horkayne-Szakaly, I., Lamperti, C., Landoure, G., Kennerson, M. L., Burnett, B. G., Bonnemann, C., Biesecker, L. G., Ghezzi, D., Zeviani, M., Fischbeck, K. H. <strong>Cowchock syndrome is associated with a mutation in apoptosis-inducing factor.</strong> Am. J. Hum. Genet. 91: 1095-1102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23217327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23217327</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23217327[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.10.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23217327">Rinaldi et al. (2012)</a> identified a hemizygous mutation in the AIFM1 gene (E493V; <a href="#0002">300169.0002</a>). The mutation was identified by exome sequencing in 1 affected family member and confirmed by Sanger sequencing to segregate with the disorder within the family. Studies of the recombinant E493V mutant protein showed some structural changes that altered the redox properties of the protein without affecting activity of the respiratory chain complexes. Patient muscle biopsy showed an increased number of apoptotic cells compared to controls, suggesting activation of the caspase-independent cell death pathway. The phenotype was characterized by early-onset axonal sensorimotor neuropathy associated in some patients with hearing loss and cognitive impairment. The findings expanded the spectrum of disorders associated with AIFM1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23217327+3856385" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 39-year-old man with X-linked recessive Charcot-Marie-Tooth disease-4 with cerebellar ataxia (CMTX4; <a href="/entry/310490">310490</a>), <a href="#2" class="mim-tip-reference" title="Ardissone, A., Piscosquito, G., Legati, A., Langella, T., Lamantea, E., Garavaglia, B., Salsano, E., Farina, L., Moroni, I., Pareyson, D., Ghezzi, D. <strong>A slowly progressive mitochondrial encephalomyopathy widens the spectrum of AIFM1 disorders.</strong> Neurology 84: 2193-2195, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25934856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25934856</a>] [<a href="https://doi.org/10.1212/WNL.0000000000001613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25934856">Ardissone et al. (2015)</a> identified a hemizygous missense mutation in the AIFM1 gene (G262S; <a href="#0014">300169.0014</a>). The mutation, which was found by sequencing of a panel of genes involved in mitochondrial disorders, was inherited from the unaffected mother. Western blot analysis of patient fibroblasts showed decreased amounts of the protein, suggesting instability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25934856" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 7 affected males from a multigenerational Irish family with CMTX4 with cerebellar ataxia, <a href="#5" class="mim-tip-reference" title="Bogdanova-Mihaylova, P., Alexander, M. D., Murphy, R. P., Chen, H., Healy, D. G., Walsh, R. A., Murphy, S. M. <strong>Clinical spectrum of AIFM1-associated disease in an Irish family, from mild neuropathy to severe cerebellar ataxia with colour blindness.</strong> J. Peripher. Nerv. Syst. 24: 348-353, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31523922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31523922</a>] [<a href="https://doi.org/10.1111/jns.12348" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31523922">Bogdanova-Mihaylova et al. (2019)</a> identified a hemizygous missense mutation in the AIFM1 gene (M340T; <a href="#0015">300169.0015</a>). The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31523922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>X-linked Deafness 5</em></strong></p><p>
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In affected members of 5 unrelated Chinese families with X-linked deafness-5 (DFNX5; <a href="/entry/300614">300614</a>), <a href="#27" class="mim-tip-reference" title="Zong, L., Guan, J., Ealy, M., Zhang, Q., Wang, D., Wang. H., Zhao, Y., Shen, Z., Campbell, C. A., Wang, F., Yang, J., Sun, W., and 18 others. <strong>Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder.</strong> J. Med. Genet. 52: 523-531, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25986071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25986071</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25986071[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/10.1136/jmedgenet-2014-102961" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25986071">Zong et al. (2015)</a> identified 5 different missense mutations in the AIFM1 gene (<a href="#0003">300169.0003</a>-<a href="#0007">300169.0007</a>). Mutations in the first 2 families were found by whole-exome sequencing and confirmed by Sanger sequencing. Screening of this gene identified the same or additional hemizygous mutations in 11 (10%) of 93 men with sporadic auditory sensory disorder. The mutations segregated with the disorder in the families, and female carriers were unaffected. Of the 11 different missense variants identified, most occurred in the NADH and second FAD domains of the protein, which are essential for FAD-dependent NADH oxidoreductase. Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25986071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>X-linked Spondyloepimetaphyseal Dysplasia With Hypomyelinating Leukodystrophy</em></strong></p><p>
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In 4 Polish brothers (family 2) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; <a href="/entry/300232">300232</a>), <a href="#17" class="mim-tip-reference" title="Mierzewska, H., Rydzanicz, M., Bieganski, T., Kosinska, J., Mierzewska-Schmidt, M., Lugowska, A., Pollak, A., Stawinski, P., Walczak, A., Kedra, A., Obersztyn, E., Ploski, R. <strong>Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation--a novel phenotype of the mitochondrial disease.</strong> Clin. Genet. 91: 30-37, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27102849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27102849</a>] [<a href="https://doi.org/10.1111/cge.12792" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27102849">Mierzewska et al. (2017)</a> identified a hemizygous missense mutation in exon 7 of the AIFM1 gene (D237G; <a href="#0008">300169.0008</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing and linkage analysis, segregated with the disorder in the family. The unaffected mother was a heterozygous carrier. The same heterozygous D237G mutation was found in an obligate carrier female from an unrelated family (family 1) in which 3 deceased males had a similar disorder (<a href="#4" class="mim-tip-reference" title="Bieganski, T., Dawydzik, B., Kozlowski, K. <strong>Spondylo-epimetaphyseal dysplasia: a new X-linked variant with mental retardation.</strong> Europ. J. Pediat. 158: 809-814, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10486082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10486082</a>] [<a href="https://doi.org/10.1007/s004310051211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10486082">Bieganski et al., 1999</a>). The mutation was not found in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in an in-house database of 1,343 individuals from the Polish population. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10486082+27102849" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 12 affected males from 6 unrelated families with SEMDHL, <a href="#18" class="mim-tip-reference" title="Miyake, N., Wolf, N. I., Cayami, F. K., Crawford, J., Bley, A., Bulas, D., Conant, A., Bent, S. J., Gripp, K. W., Hahn, A., Humphray, S., Kimura-Ohba, S., and 17 others. <strong>X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1.</strong> Neurogenetics 18: 185-194, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28842795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28842795</a>] [<a href="https://doi.org/10.1007/s10048-017-0520-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28842795">Miyake et al. (2017)</a> identified hemizygous mutations in the AIFM1 gene (see, e.g., <a href="#0008">300169.0008</a>-<a href="#0011">300169.0011</a>). The variants, which were found by whole-genome or whole-exome sequencing, either occurred de novo or were inherited from unaffected mothers. All the mutations clustered around exon 7, suggesting a specific functional impairment, and in silico analysis predicted that the variants would result in splicing defects. Analysis of fibroblasts and transdifferentiated osteoblasts derived from some patients showed decreased AIFM1 mRNA and protein levels compared to controls. <a href="#18" class="mim-tip-reference" title="Miyake, N., Wolf, N. I., Cayami, F. K., Crawford, J., Bley, A., Bulas, D., Conant, A., Bent, S. J., Gripp, K. W., Hahn, A., Humphray, S., Kimura-Ohba, S., and 17 others. <strong>X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1.</strong> Neurogenetics 18: 185-194, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28842795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28842795</a>] [<a href="https://doi.org/10.1007/s10048-017-0520-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28842795">Miyake et al. (2017)</a> concluded that AIFM1 plays a role in bone metabolism and myelination, which would account for the unique constellation of features in this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28842795" 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>Harlequin (Hq) mutant mice have progressive degeneration of terminally differentiated cerebellar and retinal neurons. <a href="#16" class="mim-tip-reference" title="Klein, J. A., Longo-Guess, C. M., Rossmann, M. P., Seburn, K. L., Hurd, R. E., Frankel, W. N., Bronson, R. T., Ackerman, S. L. <strong>The harlequin mouse mutation down-regulates apoptosis-inducing factor.</strong> Nature 419: 367-374, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12353028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12353028</a>] [<a href="https://doi.org/10.1038/nature01034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12353028">Klein et al. (2002)</a> identified the Hq mutation as a proviral insertion in the Aif gene, causing an approximately 80% reduction in Aif expression. Mutant cerebellar granular cells were susceptible to exogenous and endogenous peroxide-mediated apoptosis, but could be rescued by Aif expression. Overexpression of Aif in wildtype granule cells further decreased peroxide-mediated cell death, suggesting that AIF serves as a free radical scavenger. In agreement, dying neurons in aged Hq mutant mice showed oxidative stress. In addition, neurons damaged by oxidative stress in both the cerebellum and retina of Hq mutant mice reentered the cell cycle before undergoing apoptosis. The results of <a href="#16" class="mim-tip-reference" title="Klein, J. A., Longo-Guess, C. M., Rossmann, M. P., Seburn, K. L., Hurd, R. E., Frankel, W. N., Bronson, R. T., Ackerman, S. L. <strong>The harlequin mouse mutation down-regulates apoptosis-inducing factor.</strong> Nature 419: 367-374, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12353028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12353028</a>] [<a href="https://doi.org/10.1038/nature01034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12353028">Klein et al. (2002)</a> provided a genetic model of oxidative stress-mediated neurodegeneration and demonstrated a direct connection between cell cycle reentry and oxidative stress in the aging central nervous system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12353028" 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="#24" class="mim-tip-reference" title="Wang, X., Yang, C., Chai, J., Shi, Y., Xue, D. <strong>Mechanisms of AIF-mediated apoptotic DNA degradation in Caenorhabditis elegans.</strong> Science 298: 1587-1592, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12446902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12446902</a>] [<a href="https://doi.org/10.1126/science.1076194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12446902">Wang et al. (2002)</a> reported that inactivation of the C. elegans AIF homolog WAH-1 by RNA interference delayed the normal progression of apoptosis and caused a defect in apoptotic DNA degradation. WAH-1 localized in C. elegans mitochondria and was released into the cytosol and nucleus by the BH3-domain protein EGL1 (<a href="/entry/606266">606266</a>) in a caspase (CED3)-dependent manner. In addition, WAH-1 associated and cooperated with the mitochondrial endonuclease CPS6-endonuclease G (<a href="/entry/600440">600440</a>) to promote DNA degradation and apoptosis. Thus, AIF and EndoG define a single, mitochondria-initiated apoptotic DNA degradation pathway that is conserved between C. elegans and mammals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12446902" 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="Brown, D., Yu, B. D., Joza, N., Benit, P., Meneses, J., Firpo, M., Rustin, P., Penninger, J. M., Martin, G. R. <strong>Loss of Aif function causes cell death in the mouse embryo, but the temporal progression of patterning is normal.</strong> Proc. Nat. Acad. Sci. 103: 9918-9923, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16788063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16788063</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16788063[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/10.1073/pnas.0603950103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16788063">Brown et al. (2006)</a> found that inactivating Aif in the early mouse embryo had no effect on the apoptosis-dependent process of cavitation in embryoid bodies and apoptosis associated with embryonic neural tube closure, indicating that Aif function is not required for apoptotic cell death in early mouse embryos. By embryonic day 9, loss of Aif function caused abnormal cell death, presumably due to reduced mitochondrial respiratory chain complex-1 activity. Because of this cell death, Aif-null embryos failed to increase significantly in size after embryonic day 9. However, patterning continued on an essentially normal schedule, such that embryonic day-10 Aif-null embryos with only about 10% of the normal cell number had the same somite number as their wildtype littermates. <a href="#6" class="mim-tip-reference" title="Brown, D., Yu, B. D., Joza, N., Benit, P., Meneses, J., Firpo, M., Rustin, P., Penninger, J. M., Martin, G. R. <strong>Loss of Aif function causes cell death in the mouse embryo, but the temporal progression of patterning is normal.</strong> Proc. Nat. Acad. Sci. 103: 9918-9923, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16788063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16788063</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16788063[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/10.1073/pnas.0603950103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16788063">Brown et al. (2006)</a> concluded that pattern formation in the mouse can occur independent of embryo size and cell number. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16788063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In the rd1 mouse model of retinitis pigmentosa (see <a href="/entry/180072">180072</a>) and an in vitro cellular model, <a href="#21" class="mim-tip-reference" title="Sanges, D., Comitato, A., Tammaro, R., Marigo, V. <strong>Apoptosis in retinal degeneration involves cross-talk between apoptosis-inducing factor (AIF) and caspase-12 and is blocked by calpain inhibitors.</strong> Proc. Nat. Acad. Sci. 103: 17366-17371, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17088543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17088543</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17088543[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/10.1073/pnas.0606276103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17088543">Sanges et al. (2006)</a> found that both Aif and caspase-12 (CASP12; <a href="/entry/608633">608633</a>) translocated to the nucleus of dying photoreceptors. Only differentiated rd1 photoreceptors underwent apoptosis, and apoptosis was never observed in amacrine, bipolar, or horizontal retinal neurons. Translocation of both apoptotic factors required increased intracellular calcium, and calpain (see CAPN1; <a href="/entry/114220">114220</a>) inhibitors interfered with Aif and Casp12 activation and rd1 photoreceptor apoptosis. Knockdown of Aif or Casp12 by interfering RNA showed that Aif played a major role in this apoptotic event and that Casp12 had a reinforcing effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17088543" 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">rs387906500 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906500;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=rs387906500" 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=rs387906500" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 Italian male first-cousins, born of monozygotic twin sisters and unrelated fathers, with combined oxidative phosphorylation deficiency resulting in a severe mitochondrial encephalomyopathy (COXPD6; <a href="/entry/300816">300816</a>), <a href="#9" class="mim-tip-reference" title="Ghezzi, D., Sevrioukova, I., Invernizzi, F., Lamperti, C., Mora, M., D'Adamo, P., Novara, F., Zuffardi, O., Uziel, G., Zeviani, M. <strong>Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor.</strong> Am. J. Hum. Genet. 86: 639-649, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20362274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20362274</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20362274[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.2010.03.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20362274">Ghezzi et al. (2010)</a> identified a hemizygous 3-bp deletion (601delAGA) in the AIFM1 gene, resulting in the deletion of arg201. Both had onset in the first year of life of psychomotor regression, muscle weakness and atrophy, lack of further development, and abnormal signals in the basal ganglia. One died at age 16 months, and the other was tetraplegic and wheelchair-bound with an inability to communicate at age 5 years. In silico analysis indicated that arg201 residue is part of a hairpin that forms the FAD-binding pouch and confers conformational stability to the flavoprotein. Thus, deletion of arg201 probably perturbs the functional properties of both oxidized and reduced forms of AIF. In vitro studies showed that the lifetime of the FADH2-NAD complex formed by mutant mitochondrial AIF was shorter than that observed with wildtype. The mutant protein also had increased susceptibility to proteolytic cleavage, indicating that it is a structurally unstable variant. The mutant protein also showed higher DNA binding affinity and potential ability to cause DNA damage compared to wildtype. Approximately 75% of mutant cells versus 23% of control cells showed mitochondrial fragmentation under galactose treatment, suggesting that cells containing the mutant are more sensitive to apoptotic stimuli than control cells. Mitochondrial fragmentation was associated with impaired oxidative phosphorylation. Riboflavin treatment of cells with the mutant protein showed a recovery of the filamentous network and improvement in cell viability, which corresponded to some clinical improvement seen in 1 of the patients with the mutation. Overall, the studies showed that the AIFM1 mutation resulted in destabilization of the inner mitochondrial membrane with subsequent damage to respiratory chain structure and activities. In addition, the mutation resulted in impaired control of mitochondrion-derived programmed cell death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20362274" 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">rs281864468 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281864468;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=rs281864468" 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=rs281864468" 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=RCV000032801" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032801" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032801</a>
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<p>In affected members of the original family with Cowchock syndrome (<a href="/entry/310490">310490</a>) reported by <a href="#7" class="mim-tip-reference" title="Cowchock, F. S., Duckett, S. W., Streletz, L. J., Graziani, L. J., Jackson, L. G. <strong>X-linked motor-sensory neuropathy type-II with deafness and mental retardation: a new disorder.</strong> Am. J. Med. Genet. 20: 307-315, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3856385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3856385</a>] [<a href="https://doi.org/10.1002/ajmg.1320200214" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3856385">Cowchock et al. (1985)</a>, <a href="#20" class="mim-tip-reference" title="Rinaldi, C., Grunseich, C., Sevrioukova, I. F., Schindler, A., Horkayne-Szakaly, I., Lamperti, C., Landoure, G., Kennerson, M. L., Burnett, B. G., Bonnemann, C., Biesecker, L. G., Ghezzi, D., Zeviani, M., Fischbeck, K. H. <strong>Cowchock syndrome is associated with a mutation in apoptosis-inducing factor.</strong> Am. J. Hum. Genet. 91: 1095-1102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23217327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23217327</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23217327[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.10.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23217327">Rinaldi et al. (2012)</a> identified a hemizygous 1478A-T transversion in exon 14 of the AIFM1 gene, resulting in a glu493-to-val (E493V) substitution at a highly conserved residue. The mutation was identified by exome sequencing in 1 affected family member and confirmed by Sanger sequencing to segregate with the disorder within the family. The mutation was not found in 712 control individuals. Studies of the recombinant E493V mutant protein showed that it had a lower Km for NADH compared to wildtype, and was reduced by NADH 4-fold faster than wildtype. The charge-transfer complex had a shorter half-life than wildtype, but retained its ability to dimerize upon reduction with NADH. The mutant protein altered the redox state without affecting respiratory chain complex activity. Patient muscle biopsy showed an increased number of apoptotic cells compared to controls, suggesting activation of the caspase-independent cell death pathway. The phenotype was characterized by early-onset axonal sensorimotor neuropathy associated in some patients with hearing loss and cognitive impairment. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23217327+3856385" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 DEAFNESS, X-LINKED 5</strong>
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AIFM1, ARG451GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs863225431 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225431;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=rs863225431" 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=rs863225431" 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=RCV000202363 OR RCV002254916" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000202363, RCV002254916" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000202363...</a>
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<p>In affected male members of a large Chinese family (family AUNX1) with X-linked deafness-5 (DFNX5; <a href="/entry/300614">300614</a>), originally reported by <a href="#23" class="mim-tip-reference" title="Wang, Q. J., Li, Q. Z., Rao, S. Q., Lee, K., Huang, X. S., Yang, W. Y., Zhai, S. Q., Guo, W. W., Guo, Y. F., Yu, N., Zhao, Y. L., Yuan, H., Guan, Y., Leal, S. M., Han, D. Y., Shen, Y. <strong>AUNX1, a novel locus responsible for X linked recessive auditory and peripheral neuropathy, maps to Xq23-27.3. (Letter)</strong> J. Med. Genet. 43: e33, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16816020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16816020</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16816020[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/10.1136/jmg.2005.037929" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16816020">Wang et al. (2006)</a>, <a href="#27" class="mim-tip-reference" title="Zong, L., Guan, J., Ealy, M., Zhang, Q., Wang, D., Wang. H., Zhao, Y., Shen, Z., Campbell, C. A., Wang, F., Yang, J., Sun, W., and 18 others. <strong>Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder.</strong> J. Med. Genet. 52: 523-531, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25986071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25986071</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25986071[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/10.1136/jmedgenet-2014-102961" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25986071">Zong et al. (2015)</a> identified a hemizygous c.1352G-A transition (c.1352G-A, NM_004208.3) in exon 13 of the AIFM1 gene, resulting in an arg451-to-gln (R451Q) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project or Exome Sequencing Project databases or in 500 Chinese controls. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16816020+25986071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0004" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0004 DEAFNESS, X-LINKED 5</strong>
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AIFM1, LEU344PHE (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs184474885;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs184474885</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs184474885 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs184474885;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/rs184474885?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=rs184474885" 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=rs184474885" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000149862 OR RCV000868580 OR RCV002051816" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000149862, RCV000868580, RCV002051816" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000149862...</a>
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<p>In 2 Chinese brothers (family 0223) with X-linked deafness-5 (DFNX5; <a href="/entry/300614">300614</a>), <a href="#27" class="mim-tip-reference" title="Zong, L., Guan, J., Ealy, M., Zhang, Q., Wang, D., Wang. H., Zhao, Y., Shen, Z., Campbell, C. A., Wang, F., Yang, J., Sun, W., and 18 others. <strong>Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder.</strong> J. Med. Genet. 52: 523-531, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25986071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25986071</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25986071[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/10.1136/jmedgenet-2014-102961" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25986071">Zong et al. (2015)</a> identified a hemizygous c.1030C-T transition (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs184474885;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs184474885</a>) in exon 10 of the AIFM1 gene, resulting in a leu344-to-phe (L344F) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was annotated in the dbSNP (build 141) database at a very low frequency (0.0005), but was not found in 500 Chinese controls. Screening for AIFM1 mutations in 93 unrelated patients with sporadic auditory neuropathy revealed that 3 additional unrelated patients carried the L344F mutation. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25986071" 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">rs863225432 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225432;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=rs863225432" 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=rs863225432" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000202359" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000202359" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000202359</a>
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<p>In affected male members of a large Chinese family (family 7170) with X-linked deafness-5 (DFNX5; <a href="/entry/300614">300614</a>), <a href="#27" class="mim-tip-reference" title="Zong, L., Guan, J., Ealy, M., Zhang, Q., Wang, D., Wang. H., Zhao, Y., Shen, Z., Campbell, C. A., Wang, F., Yang, J., Sun, W., and 18 others. <strong>Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder.</strong> J. Med. Genet. 52: 523-531, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25986071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25986071</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25986071[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/10.1136/jmedgenet-2014-102961" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25986071">Zong et al. (2015)</a> identified a hemizygous c.778A-G transition (c.778A-G, NM_004208.3) in exon 7 of the AIFM1 gene, resulting in a thr260-to-ala (T260A) substitution. The variant was not found in the Exome Sequencing Project or 1000 Genomes Project databases or in 500 Chinese controls. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25986071" 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">rs724160020 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs724160020;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=rs724160020" 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=rs724160020" 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=RCV000149864 OR RCV001383393 OR RCV001532712 OR RCV001814071 OR RCV003467208 OR RCV003895033" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000149864, RCV001383393, RCV001532712, RCV001814071, RCV003467208, RCV003895033" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000149864...</a>
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<p>In 3 affected males from a Chinese family (family 2724) with X-linked deafness-5 (DFNX5; <a href="/entry/300614">300614</a>), <a href="#27" class="mim-tip-reference" title="Zong, L., Guan, J., Ealy, M., Zhang, Q., Wang, D., Wang. H., Zhao, Y., Shen, Z., Campbell, C. A., Wang, F., Yang, J., Sun, W., and 18 others. <strong>Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder.</strong> J. Med. Genet. 52: 523-531, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25986071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25986071</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25986071[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/10.1136/jmedgenet-2014-102961" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25986071">Zong et al. (2015)</a> identified a hemizygous c.1264C-T transition (c.1264C-T, NM_004208.3) in exon 12 of the AIFM1 gene, resulting in an arg422-to-trp (R422W) substitution. Two unrelated patients with sporadic disease were also found to carry the R422W mutation. The variant was not found in the Exome Sequencing Project or 1000 Genomes Project databases or in 500 Chinese controls. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25986071" 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">rs724160021 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs724160021;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=rs724160021" 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=rs724160021" 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=RCV000149865 OR RCV003467209 OR RCV003764900" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000149865, RCV003467209, RCV003764900" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000149865...</a>
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<p>In 3 affected brothers from a Chinese family (family 2423) with X-linked deafness-5 (DFNX5; <a href="/entry/300614">300614</a>), <a href="#27" class="mim-tip-reference" title="Zong, L., Guan, J., Ealy, M., Zhang, Q., Wang, D., Wang. H., Zhao, Y., Shen, Z., Campbell, C. A., Wang, F., Yang, J., Sun, W., and 18 others. <strong>Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder.</strong> J. Med. Genet. 52: 523-531, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25986071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25986071</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25986071[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/10.1136/jmedgenet-2014-102961" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25986071">Zong et al. (2015)</a> identified a hemizygous c.1265G-A transition (c.1265G-A, NM_004208.3) in exon 12 of the AIFM1 gene, resulting in an arg422-to-gln (R422Q) substitution. The variant was not found in the Exome Sequencing Project or 1000 Genomes Project databases or in 500 Chinese controls. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25986071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 SPONDYLOEPIMETAPHYSEAL DYSPLASIA, X-LINKED, WITH HYPOMYELINATING LEUKODYSTROPHY</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">rs1202786652 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1202786652;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=rs1202786652" 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=rs1202786652" 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=RCV000856716" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000856716" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000856716</a>
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<p>In 4 Polish brothers (family 2) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; <a href="/entry/300232">300232</a>), <a href="#17" class="mim-tip-reference" title="Mierzewska, H., Rydzanicz, M., Bieganski, T., Kosinska, J., Mierzewska-Schmidt, M., Lugowska, A., Pollak, A., Stawinski, P., Walczak, A., Kedra, A., Obersztyn, E., Ploski, R. <strong>Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation--a novel phenotype of the mitochondrial disease.</strong> Clin. Genet. 91: 30-37, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27102849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27102849</a>] [<a href="https://doi.org/10.1111/cge.12792" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27102849">Mierzewska et al. (2017)</a> identified a hemizygous c.710A-G transition (c.710A-G, NM_001130847.3) in exon 7 of the AIFM1 gene, resulting in an asp237-to-gly (D237G) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing and linkage analysis, segregated with the disorder in the family. The unaffected mother was a heterozygous carrier. The same heterozygous D237G mutation was found in an obligate carrier female from an unrelated family (family 1) in which 3 deceased males had a similar disorder (<a href="#4" class="mim-tip-reference" title="Bieganski, T., Dawydzik, B., Kozlowski, K. <strong>Spondylo-epimetaphyseal dysplasia: a new X-linked variant with mental retardation.</strong> Europ. J. Pediat. 158: 809-814, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10486082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10486082</a>] [<a href="https://doi.org/10.1007/s004310051211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10486082">Bieganski et al., 1999</a>). The mutation was not found in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in an in-house database of 1,343 individuals from the Polish population. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10486082+27102849" 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="#18" class="mim-tip-reference" title="Miyake, N., Wolf, N. I., Cayami, F. K., Crawford, J., Bley, A., Bulas, D., Conant, A., Bent, S. J., Gripp, K. W., Hahn, A., Humphray, S., Kimura-Ohba, S., and 17 others. <strong>X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1.</strong> Neurogenetics 18: 185-194, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28842795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28842795</a>] [<a href="https://doi.org/10.1007/s10048-017-0520-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28842795">Miyake et al. (2017)</a> identified a de novo hemizygous D237G mutation in a male patient (P4 from family 3, previously reported by <a href="#15" class="mim-tip-reference" title="Kimura-Ohba, S., Kagitani-Shimono, K., Hashimoto, N., Nabatame, S., Okinaga, T., Murakami, A., Miyake, N., Matsumoto, N., Osaka, H., Hojo, K., Tomita, R., Taniike, M., Ozono, D. <strong>A case of cerebral hypomyelination with spondylo-epi-metaphyseal dysplasia.</strong> Am. J. Med. Genet. 161A: 203-207, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23239615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23239615</a>] [<a href="https://doi.org/10.1002/ajmg.a.35686" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23239615">Kimura-Ohba et al., 2013</a>) with the disorder. The variant was found by exome sequencing and confirmed by Sanger sequencing. The patient died at age 20 years. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a splicing defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23239615+28842795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 SPONDYLOEPIMETAPHYSEAL DYSPLASIA, X-LINKED, WITH HYPOMYELINATING LEUKODYSTROPHY</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">rs1569418673 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569418673;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=rs1569418673" 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=rs1569418673" 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=RCV000735220 OR RCV000856717 OR RCV002370001" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000735220, RCV000856717, RCV002370001" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000735220...</a>
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<p>In 2 unrelated males (P1 in family 1 and P8 in family 5) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; <a href="/entry/300232">300232</a>), <a href="#18" class="mim-tip-reference" title="Miyake, N., Wolf, N. I., Cayami, F. K., Crawford, J., Bley, A., Bulas, D., Conant, A., Bent, S. J., Gripp, K. W., Hahn, A., Humphray, S., Kimura-Ohba, S., and 17 others. <strong>X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1.</strong> Neurogenetics 18: 185-194, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28842795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28842795</a>] [<a href="https://doi.org/10.1007/s10048-017-0520-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28842795">Miyake et al. (2017)</a> identified a de novo hemizygous c.720C-T transition (c.720C-T, NM_004208.3) in exon 7 of the AIFM1 gene, which was predicted to result in a synonymous asp240-to-asp (D240D) substitution. The variant, which was found by whole-genome sequencing and confirmed by Sanger sequencing, occurred de novo in patient 1 and was inherited from the unaffected mother in patient 8. The variant was not present in the dbSNP (build 147) or ExAC databases. In silico analysis predicted that the variant could result in a splicing defect, and analysis of patient-derived fibroblasts and transdifferentiated osteoblasts from patient 1 showed decreased AIFM1 mRNA and protein levels compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28842795" 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 3 male members of a family (family 4) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; <a href="/entry/300232">300232</a>), <a href="#18" class="mim-tip-reference" title="Miyake, N., Wolf, N. I., Cayami, F. K., Crawford, J., Bley, A., Bulas, D., Conant, A., Bent, S. J., Gripp, K. W., Hahn, A., Humphray, S., Kimura-Ohba, S., and 17 others. <strong>X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1.</strong> Neurogenetics 18: 185-194, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28842795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28842795</a>] [<a href="https://doi.org/10.1007/s10048-017-0520-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28842795">Miyake et al. (2017)</a> identified a hemizygous c.705G-C transversion (c.705G-C, NM_004208.3) in exon 7 of the AIFM1 gene, resulting in a gln235-to-his (Q235H) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 147) database. There was 1 female carrier of the mutation in the ExAC database. In silico analysis predicted that the variant could result in a splicing defect, and analysis of patient-derived fibroblasts and transdifferentiated osteoblasts from 1 patient showed decreased AIFM1 mRNA and protein levels compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28842795" 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">rs1603225182 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1603225182;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=rs1603225182" 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=rs1603225182" 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=RCV000856719" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000856719" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000856719</a>
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<p>In 4 male members of a family (family 6) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; <a href="/entry/300232">300232</a>), previously reported by <a href="#19" class="mim-tip-reference" title="Neubauer, B. A., Stefanova, I., Hubner, C. A., Neumaier-Probst, E., Bohl. J., Oppermann, H. C., Stoss, H., Hahn, A., Stephani, U., Kohlschutter, A., Gal, A. <strong>A new type of leukoencephalopathy with metaphyseal chondrodysplasia maps to Xq25-q27.</strong> Neurology 67: 587-591, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16924009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16924009</a>] [<a href="https://doi.org/10.1212/01.wnl.0000230133.11951.75" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16924009">Neubauer et al. (2006)</a>, <a href="#18" class="mim-tip-reference" title="Miyake, N., Wolf, N. I., Cayami, F. K., Crawford, J., Bley, A., Bulas, D., Conant, A., Bent, S. J., Gripp, K. W., Hahn, A., Humphray, S., Kimura-Ohba, S., and 17 others. <strong>X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1.</strong> Neurogenetics 18: 185-194, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28842795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28842795</a>] [<a href="https://doi.org/10.1007/s10048-017-0520-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28842795">Miyake et al. (2017)</a> identified a hemizygous T-to-G transversion (c.697-44T-G, NM_004208.3) in intron 6 of the AIFM1 gene, predicted to result in a splicing defect. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 147) or ExAC databases. Analysis of patient-derived fibroblasts and transdifferentiated osteoblasts from 1 patient showed decreased AIFM1 mRNA and protein levels compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16924009+28842795" 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">rs1603224226 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1603224226;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=rs1603224226" 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=rs1603224226" 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=RCV000907842 OR RCV003311910" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000907842, RCV003311910" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000907842...</a>
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<p>In 2 brothers with combined oxidative phosphorylation deficiency-6 (COXPD6; <a href="/entry/300816">300816</a>), <a href="#3" class="mim-tip-reference" title="Berger, I., Ben-Neriah, Z., Dor-Wolman, T., Shaag, A., Saada, A., Zenvirt, S., Raas-Rothschild, A., Nadjari, M., Kaestner, K. H., Elpeleg, O. <strong>Early prenatal ventriculomegaly due to an AIFM1 mutation identified by linkage analysis and whole exome sequencing.</strong> Molec. Genet. Metab. 104: 517-520, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22019070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22019070</a>] [<a href="https://doi.org/10.1016/j.ymgme.2011.09.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22019070">Berger et al. (2011)</a> identified a hemizygous c.923G-A transition in exon 9 of the AIFM1 gene, resulting in a gly308-to-glu (G308E) substitution at a highly conserved residue in the NADH-binding motif. The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family; the unaffected mother was a carrier. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22019070" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6</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">rs1603223152 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1603223152;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=rs1603223152" 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=rs1603223152" 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=RCV000907852" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000907852" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000907852</a>
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<p>In 2 male first cousins, born of Italian sisters, with combined oxidative phosphorylation deficiency-6 (COXPD6; <a href="/entry/300816">300816</a>), <a href="#8" class="mim-tip-reference" title="Diodato, D., Tasca, G., Verrigni, D., D'Amico, A., Rizza, T., Tozzi, G., Martinelli, D., Verardo, M., Invernizzi, F., Nasca, A., Bellachio, E., Ghezzi, D., Piemonte, F., Dionisi-Vici, C., Carrozzo, R., Bertini, E. <strong>A novel AIFM1 mutation expands the phenotype to an infantile motor neuron disease.</strong> Europ. J. Hum. Genet. 24: 463-466, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26173962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26173962</a>] [<a href="https://doi.org/10.1038/ejhg.2015.141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26173962">Diodato et al. (2016)</a> identified a hemizygous c.1013G-A transition (c.1013G-A, NM_004208.3) in the AIFM1 gene, resulting in a gly338-to-glu (G338E) substitution at a highly conserved residue. The mutation, which was found by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP (build 142) or ExAC databases. Western blot analysis of patient cells showed decreased levels of the AIFM1 protein compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26173962" 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>.0014 CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 4, WITH CEREBELLAR ATAXIA</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">rs1603224817 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1603224817;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=rs1603224817" 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=rs1603224817" 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=RCV000907854" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000907854" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000907854</a>
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<p>In a 39-year-old man with X-linked recessive Charcot-Marie-Tooth disease-4 with cerebellar ataxia (CMTX4; <a href="/entry/310490">310490</a>), <a href="#2" class="mim-tip-reference" title="Ardissone, A., Piscosquito, G., Legati, A., Langella, T., Lamantea, E., Garavaglia, B., Salsano, E., Farina, L., Moroni, I., Pareyson, D., Ghezzi, D. <strong>A slowly progressive mitochondrial encephalomyopathy widens the spectrum of AIFM1 disorders.</strong> Neurology 84: 2193-2195, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25934856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25934856</a>] [<a href="https://doi.org/10.1212/WNL.0000000000001613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25934856">Ardissone et al. (2015)</a> identified a hemizygous c.784G-A transition (c.784G-A, NM_004208) in the AIFM1 gene, resulting in a gly262-to-ser (G262S) substitution at a conserved residue. The mutation, which was found by sequencing of a panel of genes involved in mitochondrial disorders, was inherited from the unaffected mother. It was not found in the ExAC database. Western blot analysis of patient fibroblasts showed decreased amounts of the protein, suggesting instability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25934856" 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>.0015 CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 4, WITH CEREBELLAR ATAXIA</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">rs1057518895 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057518895;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=rs1057518895" 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=rs1057518895" 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=RCV000415225 OR RCV000789722 OR RCV001311404 OR RCV001385157" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000415225, RCV000789722, RCV001311404, RCV001385157" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000415225...</a>
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<p>In a 17-year-old boy (patient 1) with X-linked recessive Charcot-Marie-Tooth disease-4 with cerebellar ataxia (CMTX4; <a href="/entry/310490">310490</a>), <a href="#11" class="mim-tip-reference" title="Heimer, G., Eyal, E., Zhu, X., Ruzzo, E. K., Marek-Yagel, D., Sagiv, D., Anikster, Y., Reznik-Wolf, H., Pras, E., Levi, D. O., Lancet, D., Ben-Zeev, B., Nissenkorn, A. <strong>Mutations in AIFM1 cause an X-linked childhood cerebellar ataxia partially responsive to riboflavin.</strong> Europ. J. Paediat. Neurol. 22: 93-101, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28967629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28967629</a>] [<a href="https://doi.org/10.1016/j.ejpn.2017.09.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28967629">Heimer et al. (2018)</a> identified a c.1019T-C transition in the AIFM1 gene, resulting in a met340-to-thr (M340T) substitution at a highly conserved residue close to the NAD binding site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. It was filtered against the dbSNP (build 138), 1000 Genomes Project, Exome Sequencing Project, and ExAC databases, as well as in-house controls. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28967629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 7 affected males from a multigenerational Irish family with CMTX4 with cerebellar ataxia, <a href="#5" class="mim-tip-reference" title="Bogdanova-Mihaylova, P., Alexander, M. D., Murphy, R. P., Chen, H., Healy, D. G., Walsh, R. A., Murphy, S. M. <strong>Clinical spectrum of AIFM1-associated disease in an Irish family, from mild neuropathy to severe cerebellar ataxia with colour blindness.</strong> J. Peripher. Nerv. Syst. 24: 348-353, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31523922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31523922</a>] [<a href="https://doi.org/10.1111/jns.12348" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31523922">Bogdanova-Mihaylova et al. (2019)</a> identified a hemizygous M340T mutation. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31523922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0016 CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 4, WITH CEREBELLAR ATAXIA</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">rs1603227409 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1603227409;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=rs1603227409" 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=rs1603227409" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an 11-year-old boy (patient 2) with clinical features consistent with X-linked recessive Charcot-Marie-Tooth disease-4 with cerebellar ataxia (CMTX4; <a href="/entry/310490">310490</a>), <a href="#11" class="mim-tip-reference" title="Heimer, G., Eyal, E., Zhu, X., Ruzzo, E. K., Marek-Yagel, D., Sagiv, D., Anikster, Y., Reznik-Wolf, H., Pras, E., Levi, D. O., Lancet, D., Ben-Zeev, B., Nissenkorn, A. <strong>Mutations in AIFM1 cause an X-linked childhood cerebellar ataxia partially responsive to riboflavin.</strong> Europ. J. Paediat. Neurol. 22: 93-101, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28967629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28967629</a>] [<a href="https://doi.org/10.1016/j.ejpn.2017.09.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28967629">Heimer et al. (2018)</a> identified a de novo hemizygous c.422C-T transition in the AIFM1 gene, resulting in a thr141-to-ile (T141I) substitution at a highly conserved residue close to the FAD binding site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 138), 1000 Genomes Project, Exome Sequencing Project, and ExAC databases, as well as in-house controls. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28967629" 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>.0017 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6</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">rs1603225138 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1603225138;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=rs1603225138" 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=rs1603225138" 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=RCV000907860 OR RCV003311911" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000907860, RCV003311911" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000907860...</a>
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<p>In an 11-year-old boy with a protracted course of combined oxidative phosphorylation deficiency-6 (COXPD6; <a href="/entry/300816">300816</a>), <a href="#14" class="mim-tip-reference" title="Kettwig, M., Schubach, M., Zimmermann, F. A., Klinge, L., Mayr, J. A., Biskup, S., Sperl, W., Gartner, J., Huppke, P. <strong>From ventriculomegaly to severe muscular atrophy: expansion of the clinical spectrum related to mutations in AIFM1.</strong> Mitochondrion 21: 12-18, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25583628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25583628</a>] [<a href="https://doi.org/10.1016/j.mito.2015.01.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25583628">Kettwig et al. (2015)</a> identified a hemizygous c.727G-T transversion (c.727G-T, NM_004208.3) in exon 7 of the AIFM1 gene, resulting in a val243-to-leu (V243L) substitution at a highly conserved residue in the FAD-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. It was not found in the 1000 Genomes Project or Exome Sequencing Project. Western blot analysis of patient muscle showed reduced levels of the mutant protein, suggesting decreased stability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25583628" 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="Andrabi2006" class="mim-anchor"></a>
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Andrabi, S. A., Kim, N. S., Yu, S.-W., Wang, H., Koh, D. W., Sasaki, M., Klaus, J. A., Otsuka, T., Zhang, Z., Koehler, R. C., Hurn, P. D., Poirier, G. G., Dawson, V. L., Dawson, T. M.
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<strong>Poly(ADP-ribose) (PAR) polymer is a death signal.</strong>
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Proc. Nat. Acad. Sci. 103: 18308-18313, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17116882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17116882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17116882[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=17116882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0606526103" target="_blank">Full Text</a>]
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Ardissone, A., Piscosquito, G., Legati, A., Langella, T., Lamantea, E., Garavaglia, B., Salsano, E., Farina, L., Moroni, I., Pareyson, D., Ghezzi, D.
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<strong>A slowly progressive mitochondrial encephalomyopathy widens the spectrum of AIFM1 disorders.</strong>
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Neurology 84: 2193-2195, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25934856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25934856</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25934856" 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/10.1212/WNL.0000000000001613" target="_blank">Full Text</a>]
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<a id="Berger2011" class="mim-anchor"></a>
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Berger, I., Ben-Neriah, Z., Dor-Wolman, T., Shaag, A., Saada, A., Zenvirt, S., Raas-Rothschild, A., Nadjari, M., Kaestner, K. H., Elpeleg, O.
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<strong>Early prenatal ventriculomegaly due to an AIFM1 mutation identified by linkage analysis and whole exome sequencing.</strong>
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Molec. Genet. Metab. 104: 517-520, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22019070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22019070</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22019070" 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.ymgme.2011.09.020" target="_blank">Full Text</a>]
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Bieganski, T., Dawydzik, B., Kozlowski, K.
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<strong>Spondylo-epimetaphyseal dysplasia: a new X-linked variant with mental retardation.</strong>
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Europ. J. Pediat. 158: 809-814, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10486082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10486082</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10486082" 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/10.1007/s004310051211" target="_blank">Full Text</a>]
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Bogdanova-Mihaylova, P., Alexander, M. D., Murphy, R. P., Chen, H., Healy, D. G., Walsh, R. A., Murphy, S. M.
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<strong>Clinical spectrum of AIFM1-associated disease in an Irish family, from mild neuropathy to severe cerebellar ataxia with colour blindness.</strong>
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J. Peripher. Nerv. Syst. 24: 348-353, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31523922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31523922</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31523922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/jns.12348" target="_blank">Full Text</a>]
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Brown, D., Yu, B. D., Joza, N., Benit, P., Meneses, J., Firpo, M., Rustin, P., Penninger, J. M., Martin, G. R.
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<strong>Loss of Aif function causes cell death in the mouse embryo, but the temporal progression of patterning is normal.</strong>
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Proc. Nat. Acad. Sci. 103: 9918-9923, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16788063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16788063</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16788063[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=16788063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0603950103" target="_blank">Full Text</a>]
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<a id="Cowchock1985" class="mim-anchor"></a>
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Cowchock, F. S., Duckett, S. W., Streletz, L. J., Graziani, L. J., Jackson, L. G.
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<strong>X-linked motor-sensory neuropathy type-II with deafness and mental retardation: a new disorder.</strong>
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Am. J. Med. Genet. 20: 307-315, 1985.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3856385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3856385</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3856385" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16816020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16816020</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16816020[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=16816020" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
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[<a href="https://doi.org/10.1136/jmg.2005.037929" target="_blank">Full Text</a>]
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</p>
|
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</div>
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</li>
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<li>
|
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<a id="24" class="mim-anchor"></a>
|
|
<a id="Wang2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wang, X., Yang, C., Chai, J., Shi, Y., Xue, D.
|
|
<strong>Mechanisms of AIF-mediated apoptotic DNA degradation in Caenorhabditis elegans.</strong>
|
|
Science 298: 1587-1592, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12446902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12446902</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12446902" 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.1076194" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
|
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<a id="25" class="mim-anchor"></a>
|
|
<a id="Yu2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Yu, S.-W., Andrabi, S. A., Wang, H., Kim, N. S., Poirier, G. G., Dawson, T. M., Dawson, V. L.
|
|
<strong>Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 18314-18319, 2006.
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|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17116881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17116881</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17116881[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=17116881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0606528103" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Yu2002" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
|
Yu, S.-W., Wang, H., Poitras, M. F., Coombs, C., Bowers, W. J., Federoff, H. J., Poirier, G. G., Dawson, T. M., Dawson, V. L.
|
|
<strong>Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor.</strong>
|
|
Science 297: 259-263, 2002.
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|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12114629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12114629</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12114629" 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.1072221" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="27" class="mim-anchor"></a>
|
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<a id="Zong2015" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
Zong, L., Guan, J., Ealy, M., Zhang, Q., Wang, D., Wang. H., Zhao, Y., Shen, Z., Campbell, C. A., Wang, F., Yang, J., Sun, W., and 18 others.
|
|
<strong>Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder.</strong>
|
|
J. Med. Genet. 52: 523-531, 2015.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25986071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25986071</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25986071[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=25986071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2014-102961" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 11/26/2019
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</span>
|
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</div>
|
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</div>
|
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<div class="row collapse" id="mimCollapseContributors">
|
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 11/25/2015<br>Matthew B. Gross - updated : 1/30/2013<br>Cassandra L. Kniffin - updated : 1/29/2013<br>Cassandra L. Kniffin - updated : 4/30/2010<br>Patricia A. Hartz - updated : 2/2/2007<br>Patricia A. Hartz - updated : 12/18/2006<br>Patricia A. Hartz - updated : 8/16/2006<br>Ada Hamosh - updated : 11/25/2002<br>Ada Hamosh - updated : 10/18/2002<br>Ada Hamosh - updated : 7/24/2002<br>Ada Hamosh - updated : 4/4/2001
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
|
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Creation Date:
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
|
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Ada Hamosh : 2/5/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
|
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
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</span>
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</div>
|
|
<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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carol : 01/24/2020
|
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</span>
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</div>
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</div>
|
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<div class="row collapse" id="mimCollapseEditHistory">
|
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
alopez : 12/10/2019<br>ckniffin : 12/09/2019<br>carol : 12/02/2019<br>carol : 11/27/2019<br>ckniffin : 11/26/2019<br>carol : 12/19/2016<br>alopez : 09/19/2016<br>carol : 11/25/2015<br>ckniffin : 11/25/2015<br>carol : 4/13/2015<br>mgross : 1/30/2013<br>carol : 1/30/2013<br>ckniffin : 1/29/2013<br>wwang : 5/4/2010<br>ckniffin : 4/30/2010<br>ckniffin : 4/30/2010<br>alopez : 7/21/2009<br>alopez : 2/2/2007<br>wwang : 12/20/2006<br>terry : 12/18/2006<br>mgross : 8/25/2006<br>terry : 8/16/2006<br>alopez : 12/3/2002<br>terry : 11/25/2002<br>alopez : 10/21/2002<br>terry : 10/18/2002<br>cwells : 7/29/2002<br>terry : 7/24/2002<br>alopez : 4/5/2001<br>terry : 4/4/2001<br>alopez : 6/4/1999<br>alopez : 2/5/1999
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
|
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<h3>
|
|
<span class="mim-font">
|
|
<strong>*</strong> 300169
|
|
</span>
|
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</h3>
|
|
</div>
|
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|
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<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
APOPTOSIS-INDUCING FACTOR, MITOCHONDRIA-ASSOCIATED, 1; AIFM1
|
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|
|
</span>
|
|
</h3>
|
|
</div>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
|
<div >
|
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<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
APOPTOSIS-INDUCING FACTOR; AIF<br />
|
|
PROGRAMMED CELL DEATH 8; PDCD8
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
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<div>
|
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<br />
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</div>
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</div>
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<div>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: AIFM1</em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
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<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
|
|
<strong>SNOMEDCT:</strong> 763400005;
|
|
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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>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: Xq26.1
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : X:130,129,362-130,165,841 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
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|
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|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
Xq26.1
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Combined oxidative phosphorylation deficiency 6
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
300816
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Cowchock syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
310490
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Deafness, X-linked 5
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
300614
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
300232
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>The AIFM1 gene encodes a mitochondrial flavin adenine dinucleotide (FAD)-dependent oxidoreductase that plays a role in oxidative phosphorylation (OxPhos) and redox control in healthy cells. After mitochondrial outer membrane permeabilization, which is a feature of most, if not all, apoptotic pathways, AIFM1 is released from mitochondria and translocates to the nucleus, where it mediates nuclear features of apoptosis such as chromatin condensation and large-scale DNA degradation (summary by Joza et al., 2009). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
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<p>Susin et al. (1999) identified and cloned an apoptosis-inducing factor, AIF, that is sufficient to induce apoptosis of isolated nuclei. They cloned the mouse homolog of AIF, which has 92% amino acid identity to the human protein. The full-length proteins of both mouse and human contain 2 mitochondrial localization sequences and 2 putative nuclear localization signals. Mature mouse AIF has a molecular mass 57 kD that shares homology with the bacterial oxidoreductases, whereas the mouse precursor AIF transcript is 67 kD. AIF was normally confined to the mitochondrial intermembrane space, but translocated to the nucleus when apoptosis is induced. Recombinant AIF caused chromatin condensation and large scale fragmentation of DNA in isolated HeLa cell nuclei. It induced purified mitochondria to release the apoptogenic proteins cytochrome c (123970) and caspase-9 (602234). Microinjection of AIF into the cytoplasm of intact cells induced condensation of chromatin, dissipation of the mitochondrial transmembrane potential, and exposure of phosphatidylserine in the plasma membrane. None of the effects were prevented by pretreatment with a caspase inhibitor. Overexpression of BCL2 (151430), which controls the opening of mitochondrial permeability transition pores, prevented the release of AIF from the mitochondrion, but did not affect its apoptogenic activity. Susin et al. (1999) concluded that AIF is the principal mitochondrial factor causing nuclear apoptosis. They postulated that the caspases, DFF/CAD (601883), and AIF are engaged in complementary cooperative or redundant pathways that lead to nuclear apoptosis. </p><p>Ghezzi et al. (2010) identified human AIF as a 62-kD mature mitochondrion-specific protein that binds FAD and attaches by an N-terminal transmembrane domain to the inner mitochondrial membrane, where is functions as an NADH oxidase. Upon apoptogenic stimuli, the 57-kD soluble AIF containing 512 amino acids is released by proteolytic cleavage and translocates from the mitochondria to the nucleus, where it binds to chromosomal DNA and induces chromatin condensation and DNA fragmentation by attracting and activating a set of endonucleases. The full-length human precursor protein is a 67-kD polypeptide and contains 613 amino acids. After mitochondrial import, cleavage of a 54-amino acid mitochondrial targeting sequence results in the 62-kD mature protein containing 559 amino acids. </p><p>Zong et al. (2015) found ubiquitous expression of the Aifm1 gene in the mouse inner ear, especially in the cytoplasm of inner and outer hair cells and spiral ganglion neurons, consistent with a role in normal auditory function. </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>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>By its inclusion within a mapped clone (GenBank Z81364), Susin et al. (1999) mapped the AIFM1 gene to chromosome Xq25-q26. </p><p>Gross (2013) mapped the AIFM1 gene to chromosome Xq26.1 based on an alignment of the AIFM1 sequence (GenBank AF100928) with the genomic sequence (GRCh37).</p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Programmed cell death is a fundamental requirement for embryogenesis, organ metamorphosis, and tissue homeostasis. In mammals, release of mitochondrial cytochrome c leads to cytosolic assembly of the apoptosome--a caspase activation complex involving APAF1 (602233) and caspase-9 that induces hallmarks of apoptosis. There are, however, mitochondrially regulated cell death pathways that are independent of APAF1/caspase-9. Like cytochrome c, AIF is localized to mitochondria and released in response to death stimuli. Joza et al. (2001) showed that genetic inactivation of AIF renders embryonic stem cells resistant to cell death after serum deprivation. Moreover, AIF is essential for programmed cell death during cavitation of embryoid bodies--the very first wave of cell death indispensable for mouse morphogenesis. AIF-dependent cell death displays structural features of apoptosis, and can be genetically uncoupled from APAF1 and caspase-9 expression. Joza et al. (2001) concluded that their data provide genetic evidence for a caspase-independent pathway of programmed cell death that controls early morphogenesis. </p><p>Yu et al. (2002) demonstrated that poly(ADP-ribose) polymerase-1 (PARP1; 173870) activation is required for translocation of AIF from the mitochondria to the nucleus and that AIF is necessary for PARP1-dependent cell death. N-methyl-N-prime-nitro-N-nitrosoguanidine, hydrogen peroxide, and NMDA induce AIF translocation and cell death, which is prevented by PARP inhibitors or genetic knockout of PARP1, but is caspase independent. Microinjection of an antibody to AIF protects against PARP1-dependent cytotoxicity. Yu et al. (2002) concluded that their data support a model in which PARP1 activation signals AIF release from mitochondria, resulting in a caspase-independent pathway of programmed cell death. </p><p>Andrabi et al. (2006) and Yu et al. (2006) demonstrated that the product of PARP1 activity, poly(ADP-ribose) (PAR) polymer, mediates PARP1-induced cell death. Yu et al. (2006) showed that PAR polymer induced the release of Aif from mitochondria in mouse cortical neurons and induced its translocation to nuclei. They also showed that poly(ADP-ribose) glycohydrolase (PARG; 603501) prevented Parp1-dependent Aif release. Furthermore, cells with reduced levels of Aif were resistant to PARP1-dependent cell death and PAR polymer cytotoxicity. </p><p>Joza et al. (2009) provided a review of AIFM1 functional and animal model studies and discussed its role in caspase-independent cell death pathways, mitochondrial metabolism and redox control, and obesity and diabetes. </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>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Combined Oxidative Phosphorylation Deficiency 6</em></strong></p><p>
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In 2 Italian male first cousins, born of monozygotic twin sisters and unrelated fathers, with combined oxidative phosphorylation deficiency resulting in a severe mitochondrial encephalomyopathy (COXPD6; 300816), Ghezzi et al. (2010) identified a hemizygous deletion in the AIFM1 gene (300169.0001). Both had onset in the first year of life of psychomotor regression, muscle weakness and atrophy, lack of further development, and abnormal signals in the basal ganglia. One died at age 16 months, and the other was tetraplegic and wheelchair-bound with an inability to communicate at age 5 years. In vitro studies showed that the AIFM1 mutation resulted in destabilization of the inner mitochondrial membrane with subsequent damage to respiratory chain structure and activities. In addition, the mutation resulted in impaired control of mitochondrion-derived programmed cell death. </p><p>In 2 brothers with COXPD6, Berger et al. (2011) identified a hemizygous mutation in the AIFM1 gene (G308E; 300169.0012). The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family; the unaffected mother was a carrier. Functional studies of the variant and studies of patient cells were not performed. </p><p>In 2 male first cousins, born of Italian sisters, with COXPD6, Diodato et al. (2016) identified a hemizygous missense mutation in the AIFM1 gene (G338E; 300169.0013). The mutation, which was found by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP (build 142) or ExAC databases. Western blot analysis of patient cells showed decreased levels of the AIFM1 protein compared to controls. </p><p><strong><em>Cowchock Syndrome/X-Linked Charcot-Marie-Tooth Disease 4 With or Without Cerebellar Ataxia</em></strong></p><p>
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In affected members of the original family with Cowchock syndrome (310490), also known as X-linked recessive Charcot-Marie-Tooth disease-4 (CMTX4), reported by Cowchock et al. (1985), Rinaldi et al. (2012) identified a hemizygous mutation in the AIFM1 gene (E493V; 300169.0002). The mutation was identified by exome sequencing in 1 affected family member and confirmed by Sanger sequencing to segregate with the disorder within the family. Studies of the recombinant E493V mutant protein showed some structural changes that altered the redox properties of the protein without affecting activity of the respiratory chain complexes. Patient muscle biopsy showed an increased number of apoptotic cells compared to controls, suggesting activation of the caspase-independent cell death pathway. The phenotype was characterized by early-onset axonal sensorimotor neuropathy associated in some patients with hearing loss and cognitive impairment. The findings expanded the spectrum of disorders associated with AIFM1 mutations. </p><p>In a 39-year-old man with X-linked recessive Charcot-Marie-Tooth disease-4 with cerebellar ataxia (CMTX4; 310490), Ardissone et al. (2015) identified a hemizygous missense mutation in the AIFM1 gene (G262S; 300169.0014). The mutation, which was found by sequencing of a panel of genes involved in mitochondrial disorders, was inherited from the unaffected mother. Western blot analysis of patient fibroblasts showed decreased amounts of the protein, suggesting instability. </p><p>In 7 affected males from a multigenerational Irish family with CMTX4 with cerebellar ataxia, Bogdanova-Mihaylova et al. (2019) identified a hemizygous missense mutation in the AIFM1 gene (M340T; 300169.0015). The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. </p><p><strong><em>X-linked Deafness 5</em></strong></p><p>
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In affected members of 5 unrelated Chinese families with X-linked deafness-5 (DFNX5; 300614), Zong et al. (2015) identified 5 different missense mutations in the AIFM1 gene (300169.0003-300169.0007). Mutations in the first 2 families were found by whole-exome sequencing and confirmed by Sanger sequencing. Screening of this gene identified the same or additional hemizygous mutations in 11 (10%) of 93 men with sporadic auditory sensory disorder. The mutations segregated with the disorder in the families, and female carriers were unaffected. Of the 11 different missense variants identified, most occurred in the NADH and second FAD domains of the protein, which are essential for FAD-dependent NADH oxidoreductase. Functional studies of the variants were not performed. </p><p><strong><em>X-linked Spondyloepimetaphyseal Dysplasia With Hypomyelinating Leukodystrophy</em></strong></p><p>
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In 4 Polish brothers (family 2) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; 300232), Mierzewska et al. (2017) identified a hemizygous missense mutation in exon 7 of the AIFM1 gene (D237G; 300169.0008). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing and linkage analysis, segregated with the disorder in the family. The unaffected mother was a heterozygous carrier. The same heterozygous D237G mutation was found in an obligate carrier female from an unrelated family (family 1) in which 3 deceased males had a similar disorder (Bieganski et al., 1999). The mutation was not found in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in an in-house database of 1,343 individuals from the Polish population. Functional studies of the variant and studies of patient cells were not performed. </p><p>In 12 affected males from 6 unrelated families with SEMDHL, Miyake et al. (2017) identified hemizygous mutations in the AIFM1 gene (see, e.g., 300169.0008-300169.0011). The variants, which were found by whole-genome or whole-exome sequencing, either occurred de novo or were inherited from unaffected mothers. All the mutations clustered around exon 7, suggesting a specific functional impairment, and in silico analysis predicted that the variants would result in splicing defects. Analysis of fibroblasts and transdifferentiated osteoblasts derived from some patients showed decreased AIFM1 mRNA and protein levels compared to controls. Miyake et al. (2017) concluded that AIFM1 plays a role in bone metabolism and myelination, which would account for the unique constellation of features in this disorder. </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>Harlequin (Hq) mutant mice have progressive degeneration of terminally differentiated cerebellar and retinal neurons. Klein et al. (2002) identified the Hq mutation as a proviral insertion in the Aif gene, causing an approximately 80% reduction in Aif expression. Mutant cerebellar granular cells were susceptible to exogenous and endogenous peroxide-mediated apoptosis, but could be rescued by Aif expression. Overexpression of Aif in wildtype granule cells further decreased peroxide-mediated cell death, suggesting that AIF serves as a free radical scavenger. In agreement, dying neurons in aged Hq mutant mice showed oxidative stress. In addition, neurons damaged by oxidative stress in both the cerebellum and retina of Hq mutant mice reentered the cell cycle before undergoing apoptosis. The results of Klein et al. (2002) provided a genetic model of oxidative stress-mediated neurodegeneration and demonstrated a direct connection between cell cycle reentry and oxidative stress in the aging central nervous system. </p><p>Wang et al. (2002) reported that inactivation of the C. elegans AIF homolog WAH-1 by RNA interference delayed the normal progression of apoptosis and caused a defect in apoptotic DNA degradation. WAH-1 localized in C. elegans mitochondria and was released into the cytosol and nucleus by the BH3-domain protein EGL1 (606266) in a caspase (CED3)-dependent manner. In addition, WAH-1 associated and cooperated with the mitochondrial endonuclease CPS6-endonuclease G (600440) to promote DNA degradation and apoptosis. Thus, AIF and EndoG define a single, mitochondria-initiated apoptotic DNA degradation pathway that is conserved between C. elegans and mammals. </p><p>Brown et al. (2006) found that inactivating Aif in the early mouse embryo had no effect on the apoptosis-dependent process of cavitation in embryoid bodies and apoptosis associated with embryonic neural tube closure, indicating that Aif function is not required for apoptotic cell death in early mouse embryos. By embryonic day 9, loss of Aif function caused abnormal cell death, presumably due to reduced mitochondrial respiratory chain complex-1 activity. Because of this cell death, Aif-null embryos failed to increase significantly in size after embryonic day 9. However, patterning continued on an essentially normal schedule, such that embryonic day-10 Aif-null embryos with only about 10% of the normal cell number had the same somite number as their wildtype littermates. Brown et al. (2006) concluded that pattern formation in the mouse can occur independent of embryo size and cell number. </p><p>In the rd1 mouse model of retinitis pigmentosa (see 180072) and an in vitro cellular model, Sanges et al. (2006) found that both Aif and caspase-12 (CASP12; 608633) translocated to the nucleus of dying photoreceptors. Only differentiated rd1 photoreceptors underwent apoptosis, and apoptosis was never observed in amacrine, bipolar, or horizontal retinal neurons. Translocation of both apoptotic factors required increased intracellular calcium, and calpain (see CAPN1; 114220) inhibitors interfered with Aif and Casp12 activation and rd1 photoreceptor apoptosis. Knockdown of Aif or Casp12 by interfering RNA showed that Aif played a major role in this apoptotic event and that Casp12 had a reinforcing effect. </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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<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>17 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 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6</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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AIFM1, 3-BP DEL, 601AGA
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<br />
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SNP: rs387906500,
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ClinVar: RCV000012302
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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 Italian male first-cousins, born of monozygotic twin sisters and unrelated fathers, with combined oxidative phosphorylation deficiency resulting in a severe mitochondrial encephalomyopathy (COXPD6; 300816), Ghezzi et al. (2010) identified a hemizygous 3-bp deletion (601delAGA) in the AIFM1 gene, resulting in the deletion of arg201. Both had onset in the first year of life of psychomotor regression, muscle weakness and atrophy, lack of further development, and abnormal signals in the basal ganglia. One died at age 16 months, and the other was tetraplegic and wheelchair-bound with an inability to communicate at age 5 years. In silico analysis indicated that arg201 residue is part of a hairpin that forms the FAD-binding pouch and confers conformational stability to the flavoprotein. Thus, deletion of arg201 probably perturbs the functional properties of both oxidized and reduced forms of AIF. In vitro studies showed that the lifetime of the FADH2-NAD complex formed by mutant mitochondrial AIF was shorter than that observed with wildtype. The mutant protein also had increased susceptibility to proteolytic cleavage, indicating that it is a structurally unstable variant. The mutant protein also showed higher DNA binding affinity and potential ability to cause DNA damage compared to wildtype. Approximately 75% of mutant cells versus 23% of control cells showed mitochondrial fragmentation under galactose treatment, suggesting that cells containing the mutant are more sensitive to apoptotic stimuli than control cells. Mitochondrial fragmentation was associated with impaired oxidative phosphorylation. Riboflavin treatment of cells with the mutant protein showed a recovery of the filamentous network and improvement in cell viability, which corresponded to some clinical improvement seen in 1 of the patients with the mutation. Overall, the studies showed that the AIFM1 mutation resulted in destabilization of the inner mitochondrial membrane with subsequent damage to respiratory chain structure and activities. In addition, the mutation resulted in impaired control of mitochondrion-derived programmed cell death. </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 COWCHOCK SYNDROME</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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AIFM1, GLU493VAL
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<br />
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SNP: rs281864468,
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ClinVar: RCV000032801
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of the original family with Cowchock syndrome (310490) reported by Cowchock et al. (1985), Rinaldi et al. (2012) identified a hemizygous 1478A-T transversion in exon 14 of the AIFM1 gene, resulting in a glu493-to-val (E493V) substitution at a highly conserved residue. The mutation was identified by exome sequencing in 1 affected family member and confirmed by Sanger sequencing to segregate with the disorder within the family. The mutation was not found in 712 control individuals. Studies of the recombinant E493V mutant protein showed that it had a lower Km for NADH compared to wildtype, and was reduced by NADH 4-fold faster than wildtype. The charge-transfer complex had a shorter half-life than wildtype, but retained its ability to dimerize upon reduction with NADH. The mutant protein altered the redox state without affecting respiratory chain complex activity. Patient muscle biopsy showed an increased number of apoptotic cells compared to controls, suggesting activation of the caspase-independent cell death pathway. The phenotype was characterized by early-onset axonal sensorimotor neuropathy associated in some patients with hearing loss and cognitive impairment. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 DEAFNESS, X-LINKED 5</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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AIFM1, ARG451GLN
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<br />
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SNP: rs863225431,
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ClinVar: RCV000202363, RCV002254916
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected male members of a large Chinese family (family AUNX1) with X-linked deafness-5 (DFNX5; 300614), originally reported by Wang et al. (2006), Zong et al. (2015) identified a hemizygous c.1352G-A transition (c.1352G-A, NM_004208.3) in exon 13 of the AIFM1 gene, resulting in an arg451-to-gln (R451Q) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project or Exome Sequencing Project databases or in 500 Chinese controls. Functional studies of the variant were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 DEAFNESS, X-LINKED 5</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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AIFM1, LEU344PHE ({dbSNP rs184474885})
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<br />
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SNP: rs184474885,
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gnomAD: rs184474885,
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ClinVar: RCV000149862, RCV000868580, RCV002051816
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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 Chinese brothers (family 0223) with X-linked deafness-5 (DFNX5; 300614), Zong et al. (2015) identified a hemizygous c.1030C-T transition (rs184474885) in exon 10 of the AIFM1 gene, resulting in a leu344-to-phe (L344F) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was annotated in the dbSNP (build 141) database at a very low frequency (0.0005), but was not found in 500 Chinese controls. Screening for AIFM1 mutations in 93 unrelated patients with sporadic auditory neuropathy revealed that 3 additional unrelated patients carried the L344F mutation. Functional studies of the variant were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 DEAFNESS, X-LINKED 5</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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AIFM1, THR260ALA
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<br />
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SNP: rs863225432,
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ClinVar: RCV000202359
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected male members of a large Chinese family (family 7170) with X-linked deafness-5 (DFNX5; 300614), Zong et al. (2015) identified a hemizygous c.778A-G transition (c.778A-G, NM_004208.3) in exon 7 of the AIFM1 gene, resulting in a thr260-to-ala (T260A) substitution. The variant was not found in the Exome Sequencing Project or 1000 Genomes Project databases or in 500 Chinese controls. Functional studies of the variant were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 DEAFNESS, X-LINKED 5</strong>
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</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
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|
AIFM1, ARG422TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs724160020,
|
|
|
|
|
|
|
|
ClinVar: RCV000149864, RCV001383393, RCV001532712, RCV001814071, RCV003467208, RCV003895033
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected males from a Chinese family (family 2724) with X-linked deafness-5 (DFNX5; 300614), Zong et al. (2015) identified a hemizygous c.1264C-T transition (c.1264C-T, NM_004208.3) in exon 12 of the AIFM1 gene, resulting in an arg422-to-trp (R422W) substitution. Two unrelated patients with sporadic disease were also found to carry the R422W mutation. The variant was not found in the Exome Sequencing Project or 1000 Genomes Project databases or in 500 Chinese controls. Functional studies of the variant were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
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<div>
|
|
<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0007 DEAFNESS, X-LINKED 5</strong>
|
|
</span>
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</h4>
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</div>
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<div>
|
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<span class="mim-text-font">
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|
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|
AIFM1, ARG422GLN
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|
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|
<br />
|
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|
|
SNP: rs724160021,
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|
|
|
|
|
ClinVar: RCV000149865, RCV003467209, RCV003764900
|
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|
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|
|
</span>
|
|
</div>
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|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected brothers from a Chinese family (family 2423) with X-linked deafness-5 (DFNX5; 300614), Zong et al. (2015) identified a hemizygous c.1265G-A transition (c.1265G-A, NM_004208.3) in exon 12 of the AIFM1 gene, resulting in an arg422-to-gln (R422Q) substitution. The variant was not found in the Exome Sequencing Project or 1000 Genomes Project databases or in 500 Chinese controls. Functional studies of the variant were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
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|
<div>
|
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 SPONDYLOEPIMETAPHYSEAL DYSPLASIA, X-LINKED, WITH HYPOMYELINATING LEUKODYSTROPHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
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|
AIFM1, ASP237GLY
|
|
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|
|
<br />
|
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|
|
SNP: rs1202786652,
|
|
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|
|
|
|
ClinVar: RCV000856716
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 Polish brothers (family 2) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; 300232), Mierzewska et al. (2017) identified a hemizygous c.710A-G transition (c.710A-G, NM_001130847.3) in exon 7 of the AIFM1 gene, resulting in an asp237-to-gly (D237G) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing and linkage analysis, segregated with the disorder in the family. The unaffected mother was a heterozygous carrier. The same heterozygous D237G mutation was found in an obligate carrier female from an unrelated family (family 1) in which 3 deceased males had a similar disorder (Bieganski et al., 1999). The mutation was not found in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in an in-house database of 1,343 individuals from the Polish population. Functional studies of the variant and studies of patient cells were not performed. </p><p>Miyake et al. (2017) identified a de novo hemizygous D237G mutation in a male patient (P4 from family 3, previously reported by Kimura-Ohba et al., 2013) with the disorder. The variant was found by exome sequencing and confirmed by Sanger sequencing. The patient died at age 20 years. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a splicing defect. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
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|
<br />
|
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</div>
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</div>
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|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 SPONDYLOEPIMETAPHYSEAL DYSPLASIA, X-LINKED, WITH HYPOMYELINATING LEUKODYSTROPHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AIFM1, ASP240ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1569418673,
|
|
|
|
|
|
|
|
ClinVar: RCV000735220, RCV000856717, RCV002370001
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated males (P1 in family 1 and P8 in family 5) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; 300232), Miyake et al. (2017) identified a de novo hemizygous c.720C-T transition (c.720C-T, NM_004208.3) in exon 7 of the AIFM1 gene, which was predicted to result in a synonymous asp240-to-asp (D240D) substitution. The variant, which was found by whole-genome sequencing and confirmed by Sanger sequencing, occurred de novo in patient 1 and was inherited from the unaffected mother in patient 8. The variant was not present in the dbSNP (build 147) or ExAC databases. In silico analysis predicted that the variant could result in a splicing defect, and analysis of patient-derived fibroblasts and transdifferentiated osteoblasts from patient 1 showed decreased AIFM1 mRNA and protein levels compared to controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 SPONDYLOEPIMETAPHYSEAL DYSPLASIA, X-LINKED, WITH HYPOMYELINATING LEUKODYSTROPHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AIFM1, GLN235HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs377527583,
|
|
|
|
|
|
gnomAD: rs377527583,
|
|
|
|
|
|
ClinVar: RCV000856718
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 male members of a family (family 4) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; 300232), Miyake et al. (2017) identified a hemizygous c.705G-C transversion (c.705G-C, NM_004208.3) in exon 7 of the AIFM1 gene, resulting in a gln235-to-his (Q235H) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 147) database. There was 1 female carrier of the mutation in the ExAC database. In silico analysis predicted that the variant could result in a splicing defect, and analysis of patient-derived fibroblasts and transdifferentiated osteoblasts from 1 patient showed decreased AIFM1 mRNA and protein levels compared to controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 SPONDYLOEPIMETAPHYSEAL DYSPLASIA, X-LINKED, WITH HYPOMYELINATING LEUKODYSTROPHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AIFM1, IVS6AS, T-G, -44
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1603225182,
|
|
|
|
|
|
|
|
ClinVar: RCV000856719
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 male members of a family (family 6) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; 300232), previously reported by Neubauer et al. (2006), Miyake et al. (2017) identified a hemizygous T-to-G transversion (c.697-44T-G, NM_004208.3) in intron 6 of the AIFM1 gene, predicted to result in a splicing defect. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 147) or ExAC databases. Analysis of patient-derived fibroblasts and transdifferentiated osteoblasts from 1 patient showed decreased AIFM1 mRNA and protein levels compared to controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AIFM1, GLY308GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1603224226,
|
|
|
|
|
|
|
|
ClinVar: RCV000907842, RCV003311910
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 brothers with combined oxidative phosphorylation deficiency-6 (COXPD6; 300816), Berger et al. (2011) identified a hemizygous c.923G-A transition in exon 9 of the AIFM1 gene, resulting in a gly308-to-glu (G308E) substitution at a highly conserved residue in the NADH-binding motif. The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family; the unaffected mother was a carrier. Functional studies of the variant and studies of patient cells were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AIFM1, GLY338GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1603223152,
|
|
|
|
|
|
|
|
ClinVar: RCV000907852
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 male first cousins, born of Italian sisters, with combined oxidative phosphorylation deficiency-6 (COXPD6; 300816), Diodato et al. (2016) identified a hemizygous c.1013G-A transition (c.1013G-A, NM_004208.3) in the AIFM1 gene, resulting in a gly338-to-glu (G338E) substitution at a highly conserved residue. The mutation, which was found by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP (build 142) or ExAC databases. Western blot analysis of patient cells showed decreased levels of the AIFM1 protein compared to controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 4, WITH CEREBELLAR ATAXIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AIFM1, GLY262SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1603224817,
|
|
|
|
|
|
|
|
ClinVar: RCV000907854
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 39-year-old man with X-linked recessive Charcot-Marie-Tooth disease-4 with cerebellar ataxia (CMTX4; 310490), Ardissone et al. (2015) identified a hemizygous c.784G-A transition (c.784G-A, NM_004208) in the AIFM1 gene, resulting in a gly262-to-ser (G262S) substitution at a conserved residue. The mutation, which was found by sequencing of a panel of genes involved in mitochondrial disorders, was inherited from the unaffected mother. It was not found in the ExAC database. Western blot analysis of patient fibroblasts showed decreased amounts of the protein, suggesting instability. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 4, WITH CEREBELLAR ATAXIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AIFM1, MET340THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1057518895,
|
|
|
|
|
|
|
|
ClinVar: RCV000415225, RCV000789722, RCV001311404, RCV001385157
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 17-year-old boy (patient 1) with X-linked recessive Charcot-Marie-Tooth disease-4 with cerebellar ataxia (CMTX4; 310490), Heimer et al. (2018) identified a c.1019T-C transition in the AIFM1 gene, resulting in a met340-to-thr (M340T) substitution at a highly conserved residue close to the NAD binding site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. It was filtered against the dbSNP (build 138), 1000 Genomes Project, Exome Sequencing Project, and ExAC databases, as well as in-house controls. Functional studies of the variant and studies of patient cells were not performed. </p><p>In 7 affected males from a multigenerational Irish family with CMTX4 with cerebellar ataxia, Bogdanova-Mihaylova et al. (2019) identified a hemizygous M340T mutation. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 4, WITH CEREBELLAR ATAXIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AIFM1, THR141ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1603227409,
|
|
|
|
|
|
|
|
ClinVar: RCV000907858
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 11-year-old boy (patient 2) with clinical features consistent with X-linked recessive Charcot-Marie-Tooth disease-4 with cerebellar ataxia (CMTX4; 310490), Heimer et al. (2018) identified a de novo hemizygous c.422C-T transition in the AIFM1 gene, resulting in a thr141-to-ile (T141I) substitution at a highly conserved residue close to the FAD binding site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 138), 1000 Genomes Project, Exome Sequencing Project, and ExAC databases, as well as in-house controls. Functional studies of the variant and studies of patient cells were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AIFM1, VAL243LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1603225138,
|
|
|
|
|
|
|
|
ClinVar: RCV000907860, RCV003311911
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 11-year-old boy with a protracted course of combined oxidative phosphorylation deficiency-6 (COXPD6; 300816), Kettwig et al. (2015) identified a hemizygous c.727G-T transversion (c.727G-T, NM_004208.3) in exon 7 of the AIFM1 gene, resulting in a val243-to-leu (V243L) substitution at a highly conserved residue in the FAD-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. It was not found in the 1000 Genomes Project or Exome Sequencing Project. Western blot analysis of patient muscle showed reduced levels of the mutant protein, suggesting decreased stability. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
|
|
</div>
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|
<div>
|
|
<h4>
|
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 11/26/2019<br>Cassandra L. Kniffin - updated : 11/25/2015<br>Matthew B. Gross - updated : 1/30/2013<br>Cassandra L. Kniffin - updated : 1/29/2013<br>Cassandra L. Kniffin - updated : 4/30/2010<br>Patricia A. Hartz - updated : 2/2/2007<br>Patricia A. Hartz - updated : 12/18/2006<br>Patricia A. Hartz - updated : 8/16/2006<br>Ada Hamosh - updated : 11/25/2002<br>Ada Hamosh - updated : 10/18/2002<br>Ada Hamosh - updated : 7/24/2002<br>Ada Hamosh - updated : 4/4/2001
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</span>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh : 2/5/1999
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carol : 01/24/2020<br>alopez : 12/10/2019<br>ckniffin : 12/09/2019<br>carol : 12/02/2019<br>carol : 11/27/2019<br>ckniffin : 11/26/2019<br>carol : 12/19/2016<br>alopez : 09/19/2016<br>carol : 11/25/2015<br>ckniffin : 11/25/2015<br>carol : 4/13/2015<br>mgross : 1/30/2013<br>carol : 1/30/2013<br>ckniffin : 1/29/2013<br>wwang : 5/4/2010<br>ckniffin : 4/30/2010<br>ckniffin : 4/30/2010<br>alopez : 7/21/2009<br>alopez : 2/2/2007<br>wwang : 12/20/2006<br>terry : 12/18/2006<br>mgross : 8/25/2006<br>terry : 8/16/2006<br>alopez : 12/3/2002<br>terry : 11/25/2002<br>alopez : 10/21/2002<br>terry : 10/18/2002<br>cwells : 7/29/2002<br>terry : 7/24/2002<br>alopez : 4/5/2001<br>terry : 4/4/2001<br>alopez : 6/4/1999<br>alopez : 2/5/1999
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