6524 lines
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Entry
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- *608507 - MITOFUSIN 2; MFN2
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*608507</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/608507">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000116688;t=ENST00000235329" 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=9927" 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=608507" 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 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=ENSG00000116688;t=ENST00000235329" 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_001127660,NM_014874,XM_005263543,XM_005263545,XM_005263548,XM_047436149,XM_047436154,XM_047436156" 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_014874" 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=608507" 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=08495&isoform_id=08495_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/MFN2" 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/7662004,16168681,16877627,19879248,47605777,50978456,119592132,119592133,158260679,189083768,193785498,193785627,193785640,221041074,530360735,530360739,530360745,929653836,2217272858,2217272861,2217272864,2462516097,2462516099,2462516101,2462516103,2462516105,2462516107" 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/O95140" 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=9927" 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=ENSG00000116688;t=ENST00000235329" 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=MFN2" 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=MFN2" 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+9927" 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/MFN2" 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:9927" 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/9927" 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=chr1&hgg_gene=ENST00000235329.10&hgg_start=11980444&hgg_end=12013508&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:16877" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:16877" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/mfn2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=608507[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=608507[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/MFN2/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/ENSG00000116688" 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=MFN2" 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=MFN2" 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=MFN2" 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.molgen.ua.ac.be/CMTMutations/" 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=MFN2&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/PA134986046" 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:16877" 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/FBgn0029870.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:2442230" 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/MFN2#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:2442230" 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/9927/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://omia.org/results?search_type=advanced&omia_id=000715,001106,002153" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=9927" 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=WBGene00001509;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-081105-44" 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:9927" 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=MFN2&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> 128203003, 238902007<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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608507
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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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MITOFUSIN 2; MFN2
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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">
|
|
KIAA0214
|
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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=MFN2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MFN2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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<strong>
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<em>
|
|
Cytogenetic location: <a href="/geneMap/1/163?start=-3&limit=10&highlight=163">1p36.22</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:11980444-12013508&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'})">1:11,980,444-12,013,508</a> </span>
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</em>
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=609260,617087,601152,151800" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/163?start=-3&limit=10&highlight=163">
|
|
1p36.22
|
|
</a>
|
|
</span>
|
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</td>
|
|
|
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|
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<td>
|
|
<span class="mim-font">
|
|
Charcot-Marie-Tooth disease, axonal, type 2A2A
|
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|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/609260"> 609260 </a>
|
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|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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<p>The size and arrangement of mitochondria differs with cell type, physiologic condition, and pathologic state. Mitofusins, such as MFN2, mediate the fusion of mitochondria and thereby contribute to the dynamic balance between fusion and fission that determines mitochondria morphology (<a href="#35" class="mim-tip-reference" title="Santel, A., Fuller, M. T. <strong>Control of mitochondrial morphology by a human mitofusin.</strong> J. Cell Sci. 114: 867-874, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11181170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11181170</a>] [<a href="https://doi.org/10.1242/jcs.114.5.867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11181170">Santel and Fuller, 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11181170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By sequencing clones obtained from a size-fractionated immature myeloid cell line cDNA library, <a href="#26" class="mim-tip-reference" title="Nagase, T., Seki, N., Ishikawa, K., Ohira, M., Kawarabayasi, Y., Ohara, O., Tanaka, A., Kotani, H., Miyajima, N., Nomura, N. <strong>Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain.</strong> DNA Res. 3: 321-329, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9039502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9039502</a>] [<a href="https://doi.org/10.1093/dnares/3.5.321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9039502">Nagase et al. (1996)</a> cloned MFN2, which they designated KIAA0214. The deduced 757-amino acid protein contains an ATP/GTP-binding site motif. Northern blot analysis detected expression of MFN2 in all tissues and cell lines examined, with highest expression in heart and skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9039502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By searching EST databases, <a href="#35" class="mim-tip-reference" title="Santel, A., Fuller, M. T. <strong>Control of mitochondrial morphology by a human mitofusin.</strong> J. Cell Sci. 114: 867-874, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11181170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11181170</a>] [<a href="https://doi.org/10.1242/jcs.114.5.867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11181170">Santel and Fuller (2001)</a> found that KIAA0214 showed significant similarity to the Drosophila mitochondria fusion gene, Fzo, and they further characterized the cDNA clone. The deduced 757-amino acid protein contains an N-terminal GTPase domain and a transmembrane domain near the C terminus. MFN2 shares 60% identity with MFN1 (<a href="/entry/608506">608506</a>), with the most extensive homology in the GTPase domains. The N- and C-terminal ends are more variable. When stably expressed in COS-7 cells, MFN2 colocalized with mitochondrial markers. An internal region, including the predicted bipartite transmembrane domain, was sufficient to target MFN2 to mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11181170" 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="Bach, D., Pich, S., Soriano, F. X., Vega, N., Baumgartner, B., Oriola, J., Daugaard, J. R., Lloberas, J., Camps, M., Zierath, J. R., Rabasa-Lhoret, R., Wallberg-Henriksson, H., Laville, M., Palacin, M., Vidal, H., Rivera, F., Brand, M., Zorzano, A. <strong>Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism: a novel regulatory mechanism altered in obesity.</strong> J. Biol. Chem. 278: 17190-17197, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12598526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12598526</a>] [<a href="https://doi.org/10.1074/jbc.M212754200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12598526">Bach et al. (2003)</a> cloned rat Mfn2, which shares 95% identity to human MFN2. Northern blot analysis of human tissues detected a 4.7-kb transcript expressed at high levels in skeletal muscle and heart, and at lower levels in brain, kidney, and liver. Little to no expression was detected in other tissues. Very little Mfn2 was expressed in a rat myoblast cell line, but expression was induced following differentiation into myotubes. Western blot analysis detected rat Mfn2 at an apparent molecular mass of 110 kD in heart, skeletal muscle, brown adipose tissue, and kidney. Endogenous Mfn2 was enriched in mitochondrial fractions of these tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12598526" 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="#8" class="mim-tip-reference" title="Casasnovas, C., Banchs, I., Cassereau, J., Gueguen, N., Chevrollier, A., Martinez-Matos, J. A., Bonneau, D., Volpini, V. <strong>Phenotypic spectrum of MFN2 mutations in the Spanish population.</strong> J. Med. Genet. 47: 249-256, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19889647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19889647</a>] [<a href="https://doi.org/10.1136/jmg.2009.072488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19889647">Casasnovas et al. (2010)</a> noted that the MFN2 gene contains 19 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19889647" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By radiation hybrid analysis and by examining a human-rodent hybrid panel, <a href="#26" class="mim-tip-reference" title="Nagase, T., Seki, N., Ishikawa, K., Ohira, M., Kawarabayasi, Y., Ohara, O., Tanaka, A., Kotani, H., Miyajima, N., Nomura, N. <strong>Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain.</strong> DNA Res. 3: 321-329, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9039502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9039502</a>] [<a href="https://doi.org/10.1093/dnares/3.5.321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9039502">Nagase et al. (1996)</a> mapped the MFN2 gene to chromosome 1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9039502" 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="#42" class="mim-tip-reference" title="Zuchner, S., Mersiyanova, I. V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali, E. L., Zappia, M., Nelis, E., Patitucci, A., Senderek, J., Parman, Y., Evgrafov, O., and 10 others. <strong>Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.</strong> Nature Genet. 36: 449-451, 2004. Note: Erratum: Nature Genet. 36: 660 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15064763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15064763</a>] [<a href="https://doi.org/10.1038/ng1341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15064763">Zuchner et al. (2004)</a> stated that the MFN2 gene maps to chromosome 1p36.2, about 1.65 Mb centromeric to the KIF1B gene (<a href="/entry/605995">605995</a>), which is mutant in Charcot-Marie-Tooth disease-2A1 (CMT2A1; <a href="/entry/118210">118210</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15064763" 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="#35" class="mim-tip-reference" title="Santel, A., Fuller, M. T. <strong>Control of mitochondrial morphology by a human mitofusin.</strong> J. Cell Sci. 114: 867-874, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11181170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11181170</a>] [<a href="https://doi.org/10.1242/jcs.114.5.867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11181170">Santel and Fuller (2001)</a> found that overexpression of MFN2 caused perinuclear mitochondrial clustering. Mutation analysis revealed that the C-terminal coiled-coil domain mediated mitochondrial clustering, and the GTPase domain mediated mitochondrial fusion. Furthermore, a GTPase-dead DRP1 (<a href="/entry/603850">603850</a>) caused similar mitochondrial clustering in transfected COS-7 cells, and COS-7 cells cotransfected with the GTPase-dead DRP1 and MFN2 developed mitochondrial filaments and networks that extended from the perinuclear mitochondrial cluster toward the cell periphery. <a href="#35" class="mim-tip-reference" title="Santel, A., Fuller, M. T. <strong>Control of mitochondrial morphology by a human mitofusin.</strong> J. Cell Sci. 114: 867-874, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11181170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11181170</a>] [<a href="https://doi.org/10.1242/jcs.114.5.867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11181170">Santel and Fuller (2001)</a> concluded that the size and morphologic arrangement of mitochondria are due to a dynamic balance between MFN-dependent mitochondrial fusion and DRP1-dependent mitochondrial fission. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11181170" 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="Bach, D., Pich, S., Soriano, F. X., Vega, N., Baumgartner, B., Oriola, J., Daugaard, J. R., Lloberas, J., Camps, M., Zierath, J. R., Rabasa-Lhoret, R., Wallberg-Henriksson, H., Laville, M., Palacin, M., Vidal, H., Rivera, F., Brand, M., Zorzano, A. <strong>Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism: a novel regulatory mechanism altered in obesity.</strong> J. Biol. Chem. 278: 17190-17197, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12598526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12598526</a>] [<a href="https://doi.org/10.1074/jbc.M212754200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12598526">Bach et al. (2003)</a> found that the induction of Mfn2 during differentiation in a rat myogenic cell line into myotubes paralleled the development of an extensive mitochondrial network. Overexpression of Mfn2 collapsed the network and mitochondria clustered around the nucleus. Knock-down of Mfn2 expression in muscle cells with mouse Mfn2 antisense sequence led to fragmentation of the mitochondrial network into independent clusters and loss of mitochondrial membrane potential. Reduced Mfn2 expression in rat myotubes and mouse fibroblasts was associated with a 30% reduction of glucose oxidation. Repression of Mfn2 expression also reduced mitochondrial membrane potential and cell respiration, and reduced mitochondrial proton leak. <a href="#1" class="mim-tip-reference" title="Bach, D., Pich, S., Soriano, F. X., Vega, N., Baumgartner, B., Oriola, J., Daugaard, J. R., Lloberas, J., Camps, M., Zierath, J. R., Rabasa-Lhoret, R., Wallberg-Henriksson, H., Laville, M., Palacin, M., Vidal, H., Rivera, F., Brand, M., Zorzano, A. <strong>Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism: a novel regulatory mechanism altered in obesity.</strong> J. Biol. Chem. 278: 17190-17197, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12598526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12598526</a>] [<a href="https://doi.org/10.1074/jbc.M212754200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12598526">Bach et al. (2003)</a> further found that Mfn2 expression was repressed in obesity, being reduced by 34% in muscle from obese rats, and reduced by 36% in muscle of obese human subjects. Expression in mitochondrial fractions was 39% lower in obese rats, and 43% lower in obese humans in comparison with lean controls. <a href="#1" class="mim-tip-reference" title="Bach, D., Pich, S., Soriano, F. X., Vega, N., Baumgartner, B., Oriola, J., Daugaard, J. R., Lloberas, J., Camps, M., Zierath, J. R., Rabasa-Lhoret, R., Wallberg-Henriksson, H., Laville, M., Palacin, M., Vidal, H., Rivera, F., Brand, M., Zorzano, A. <strong>Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism: a novel regulatory mechanism altered in obesity.</strong> J. Biol. Chem. 278: 17190-17197, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12598526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12598526</a>] [<a href="https://doi.org/10.1074/jbc.M212754200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12598526">Bach et al. (2003)</a> concluded that MFN2 expression is crucial in mitochondrial metabolism through the maintenance of the mitochondrial network architecture, and reduced MFN2 expression may explain some of the metabolic alterations associated with obesity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12598526" 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="#29" class="mim-tip-reference" title="Pich, S., Bach, D., Briones, P., Liesa, M., Camps, M., Testar, X., Palacin, M., Zorzano, A. <strong>The Charcot-Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system.</strong> Hum. Molec. Genet. 14: 1405-1415, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15829499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15829499</a>] [<a href="https://doi.org/10.1093/hmg/ddi149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15829499">Pich et al. (2005)</a> showed that Mfn2 loss of function inhibited pyruvate, glucose, and fatty acid oxidation and reduced mitochondrial membrane potential, whereas Mfn2 gain of function increased glucose oxidation and mitochondrial membrane potential. Mfn2 loss of function repressed nuclear-encoded subunits of OXPHOS complexes I, II, III and V, whereas Mfn2 overexpression induced the subunits of complexes I, IV, and V. Obesity-induced Mfn2 deficiency in rat skeletal muscle was also associated with a decrease in the subunits of complexes I, II, III, and V. In addition, the effect of Mfn2 overexpression on mitochondrial metabolism was mimicked by a truncated Mfn2 mutant that was inactive as a mitochondrial fusion protein. <a href="#29" class="mim-tip-reference" title="Pich, S., Bach, D., Briones, P., Liesa, M., Camps, M., Testar, X., Palacin, M., Zorzano, A. <strong>The Charcot-Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system.</strong> Hum. Molec. Genet. 14: 1405-1415, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15829499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15829499</a>] [<a href="https://doi.org/10.1093/hmg/ddi149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15829499">Pich et al. (2005)</a> concluded that Mfn2 triggers mitochondrial energization, at least in part, by regulating OXPHOS expression through signals that are independent of its role as a mitochondrial fusion protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15829499" 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>Two members of the BCL2 family, BAX (<a href="/entry/600040">600040</a>) and BAK (<a href="/entry/600516">600516</a>), change intracellular location early in the promotion of apoptosis to concentrate in focal clusters at sites of mitochondrial division. <a href="#20" class="mim-tip-reference" title="Karbowski, M., Norris, K. L., Cleland, M. M., Jeong, S.-Y., Youle, R. J. <strong>Role of Bax and Bak in mitochondrial morphogenesis.</strong> Nature 443: 658-662, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17035996/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17035996</a>] [<a href="https://doi.org/10.1038/nature05111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17035996">Karbowski et al. (2006)</a> reported that in healthy cells, BAX or BAK is required for normal fusion of mitochondria into elongated tubules. BAX seems to induce mitochondrial fusion by activating assembly of the large GTPase MFN2 and changing its submitochondrial distribution and membrane mobility--properties that correlate with different GTP-bound states of MFN2. <a href="#20" class="mim-tip-reference" title="Karbowski, M., Norris, K. L., Cleland, M. M., Jeong, S.-Y., Youle, R. J. <strong>Role of Bax and Bak in mitochondrial morphogenesis.</strong> Nature 443: 658-662, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17035996/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17035996</a>] [<a href="https://doi.org/10.1038/nature05111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17035996">Karbowski et al. (2006)</a> concluded that BAX and BAK regulate mitochondrial dynamics in healthy cells and that BCL2 family members may also regulate apoptosis through organelle morphogenesis machineries. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17035996" 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="#19" class="mim-tip-reference" title="Guo, X., Chen, K.-H., Guo, Y., Liao, H., Tang, J., Xiao, R.-P. <strong>Mitofusin 2 triggers vascular smooth muscle cell apoptosis via mitochondrial death pathway.</strong> Circ. Res. 101: 1113-1122, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17901359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17901359</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.107.157644" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17901359">Guo et al. (2007)</a> found that a variety of apoptotic stimuli induced expression of Mfn2 in rat vascular smooth muscle cells (VSMCs). Overexpression of Mfn2 triggered apoptosis of VSMCs in culture and in balloon-injured rat carotid arteries, which helped prevent neointima formation after angioplasty. Conversely, Mfn2 silencing protected VSMCs against H2O2- or Mfn2 overexpression-induced apoptosis. The proapoptotic effect of Mfn2 was independent of its role in mitochondrial fusion and was mediated by inhibition of Akt (see AKT1; <a href="/entry/164730">164730</a>) signaling, resulting in activation of the mitochondrial apoptotic pathway. Mfn2-induced apoptosis was blocked by overexpression of an active phosphoinositide 3-kinase (see PIK3CG; <a href="/entry/601232">601232</a>) mutant or inhibition of Bclxl (<a href="/entry/600039">600039</a>) or caspase-9 (CASP9; <a href="/entry/602234">602234</a>). <a href="#19" class="mim-tip-reference" title="Guo, X., Chen, K.-H., Guo, Y., Liao, H., Tang, J., Xiao, R.-P. <strong>Mitofusin 2 triggers vascular smooth muscle cell apoptosis via mitochondrial death pathway.</strong> Circ. Res. 101: 1113-1122, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17901359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17901359</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.107.157644" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17901359">Guo et al. (2007)</a> concluded that, in addition to its antiproliferative effects, MFN2 is a primary determinant of VSMC apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17901359" 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="de Brito, O. M., Scorrano, L. <strong>Mitofusin 2 tethers endoplasmic reticulum to mitochondria.</strong> Nature 456: 605-610, 2008. Note: Erratum: Nature 513: 266 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19052620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19052620</a>] [<a href="https://doi.org/10.1038/nature07534" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19052620">De Brito and Scorrano (2008)</a> showed that MFN2 is enriched at the endoplasmic reticulum (ER)-mitochondria interface. Ablation or silencing of Mfn2 in mouse embryonic fibroblasts and HeLa cells disrupted ER morphology and loosened ER-mitochondria interactions, thereby reducing the efficiency of mitochondrial calcium uptake in response to stimuli that generate inositol-1,4,5-trisphosphate. An in vitro assay as well as genetic and biochemical evidences supported a model in which Mfn2 on the ER bridges the 2 organelles by engaging in homotypic and heterotypic complexes with Mfn1 (<a href="/entry/608506">608506</a>) or Mfn2 on the surface of mitochondria. Thus, <a href="#12" class="mim-tip-reference" title="de Brito, O. M., Scorrano, L. <strong>Mitofusin 2 tethers endoplasmic reticulum to mitochondria.</strong> Nature 456: 605-610, 2008. Note: Erratum: Nature 513: 266 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19052620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19052620</a>] [<a href="https://doi.org/10.1038/nature07534" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19052620">de Brito and Scorrano (2008)</a> concluded that Mfn2 tethers ER to mitochondria, a juxtaposition required for efficient mitochondrial calcium uptake. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19052620" 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="Chen, Y., Dorn, G. W., II. <strong>PINK1-phosphorylated mitofusin 2 is a parkin receptor for culling damaged mitochondria.</strong> Science 340: 471-475, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23620051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23620051</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23620051[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1231031" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23620051">Chen and Dorn (2013)</a> demonstrated that the mitochondrial outer membrane guanosine triphosphatase MFN2 mediates parkin (<a href="/entry/602544">602544</a>) recruitment to damaged mitochondria. Parkin bound to MFN2 in a PINK1 (<a href="/entry/608309">608309</a>)-dependent manner; PINK1 phosphorylated MFN2 and promoted its parkin-mediated ubiquitination. Ablation of Mfn2 in mouse cardiac myocytes prevented depolarization-induced translocation of parkin to the mitochondria and suppressed mitophagy. Accumulation of morphologically and functionally abnormal mitochondria induced respiratory dysfunction in Mfn2-deficient mouse embryonic fibroblasts and cardiomyocytes and in parkin-deficient Drosophila heart tubes, causing dilated cardiomyopathy. Thus, <a href="#10" class="mim-tip-reference" title="Chen, Y., Dorn, G. W., II. <strong>PINK1-phosphorylated mitofusin 2 is a parkin receptor for culling damaged mitochondria.</strong> Science 340: 471-475, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23620051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23620051</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23620051[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1231031" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23620051">Chen and Dorn (2013)</a> concluded that MFN2 functions as a mitochondrial receptor for parkin and is required for quality control of cardiac mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23620051" 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="#21" class="mim-tip-reference" title="Kasahara, A., Cipolat, S., Chen, Y., Dorn, G. W., II, Scorrano, L. <strong>Mitochondrial fusion directs cardiomyocyte differentiation via calcineurin and Notch signaling.</strong> Science 342: 734-737, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24091702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24091702</a>] [<a href="https://doi.org/10.1126/science.1241359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24091702">Kasahara et al. (2013)</a> found that mitochondrial fusion was required for proper cardiomyocyte development. Ablation of mitochondrial fusion proteins Mfn1 and Mfn2 in the embryonic mouse heart, or gene trapping of Mfn2 or optic atrophy-1 (Opa1; <a href="/entry/605290">605290</a>) in mouse embryonic stem cells, arrested mouse heart development and impaired differentiation of embryonic stem cells into cardiomyocytes. Gene expression profiling revealed decreased levels of transcription factors Tgf-beta (<a href="/entry/190180">190180</a>)/Bmp (see <a href="/entry/112264">112264</a>), serum response factor (SRF; <a href="/entry/600589">600589</a>), Gata4 (<a href="/entry/600576">600576</a>), and myocyte enhancer factor-2, linked to increased calcium-dependent calcineurin (see <a href="/entry/114105">114105</a>) activity and Notch1 (<a href="/entry/190198">190198</a>) signaling that impaired embryonic stem cell differentiation. <a href="#21" class="mim-tip-reference" title="Kasahara, A., Cipolat, S., Chen, Y., Dorn, G. W., II, Scorrano, L. <strong>Mitochondrial fusion directs cardiomyocyte differentiation via calcineurin and Notch signaling.</strong> Science 342: 734-737, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24091702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24091702</a>] [<a href="https://doi.org/10.1126/science.1241359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24091702">Kasahara et al. (2013)</a> concluded that orchestration of cardiomyocyte differentiation by mitochondrial morphology revealed how mitochondria, calcium, and calcineurin interact to regulate Notch1 signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24091702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using RT-PCR analysis, <a href="#38" class="mim-tip-reference" title="Vadnais, M. L., Lin, A. M., Gerton, G. L. <strong>Mitochondrial fusion protein MFN2 interacts with the mitostatin-related protein MNS1 required for mouse sperm flagellar structure and function.</strong> Cilia 3: 5, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24876927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24876927</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24876927[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/10.1186/2046-2530-3-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24876927">Vadnais et al. (2014)</a> showed that Mns1 (<a href="/entry/610766">610766</a>) and Mfn2 were highly expressed in mouse spermatogenic cells, with decreasing expression from pachytene spermatocytes to condensing spermatids. In spermatogenic cells, Mfn2 was expressed in mitochondria, and Mns1 in cytoplasm. Both proteins were also found in caput and cauda epididymal sperm and in male and female reproductive tissues. Immunoprecipitation and immunofluorescence analyses revealed that both proteins formed a complex in spermatogenic cells and colocalized to sperm flagellum. The results demonstrated that Mns1 and Mfn2 are an integral part of sperm flagellum and suggested that they play a role in flagellar biogenesis and/or function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24876927" 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="Luchsinger, L. L., de Almeida, M. J., Corrigan, D. J., Mumau, M., Snoeck, H.-W. <strong>Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential.</strong> Nature 529: 528-531, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26789249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26789249</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26789249[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/10.1038/nature16500" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26789249">Luchsinger et al. (2016)</a> showed in mice that the short isoform of a critical regulator of hematopoietic stem cells (HSCs), Prdm16 (<a href="/entry/605557">605557</a>), induces Mfn2, a protein involved in mitochondrial fusion and in tethering of mitochondria to the endoplasmic reticulum. Overexpression and deletion studies, including single-cell transplantation assays, revealed that Mfn2 is specifically required for the maintenance of HSCs with extensive lymphoid potential, but not, or less so, for the maintenance of myeloid-dominant HSCs. Mfn2 increased buffering of intracellular Ca(2+), an effect mediated through its endoplasmic reticulum-mitochondria tethering activity, thereby negatively regulating nuclear translocation and transcriptional activity of nuclear factor of activated T cells (Nfat; see <a href="/entry/600489">600489</a>). Nfat inhibition rescued the effects of Mfn2 deletion in HSCs, demonstrating that negative regulation of Nfat is the prime downstream mechanism of Mfn2 in the maintenance of HSCs with extensive lymphoid potential. Mitochondria therefore have an important role in HSCs. <a href="#24" class="mim-tip-reference" title="Luchsinger, L. L., de Almeida, M. J., Corrigan, D. J., Mumau, M., Snoeck, H.-W. <strong>Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential.</strong> Nature 529: 528-531, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26789249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26789249</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26789249[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/10.1038/nature16500" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26789249">Luchsinger et al. (2016)</a> concluded that these findings provided a mechanism underlying clonal heterogeneity among HSCs and could lead to the design of approaches to bias HSC differentiation into desired lineages after transplantation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26789249" 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="#32" class="mim-tip-reference" title="Rocha, A. G., Franco, A., Krezel, A. M., Rumsey, J. M., Alberti, J. M., Knight, W. C., Biris, N., Zacharioudakis, E., Janetka, J. W., Baloh, R. H., Kitsis, R. N., Mochly-Rosen, D., Townsend, R. R., Gavathiotis, E., Dorn, G. W., II. <strong>MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A.</strong> Science 360: 336-341, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29674596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29674596</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29674596[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aao1785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29674596">Rocha et al. (2018)</a> showed that MFN2 activity can be determined by met376 and his380 interactions with asp725 and leu727 and controlled by PINK1 kinase-mediated phosphorylation of adjacent MFN2 ser378. Small-molecule mimics of the peptide-peptide interface of MFN2 disrupted this interaction, allosterically activating MFN2 and promoting mitochondrial fusion. These first-in-class mitofusin agonists overcame dominant mitochondrial defects provoked in cultured neurons by CMT2A mutants MFN2 arg94 to gln (<a href="#0001">608507.0001</a>) and MFN2 thr105 to met (T105M), as demonstrated by amelioration of mitochondrial dysmotility, fragmentation, depolarization, and clumping. A mitofusin agonist normalized axonal mitochondrial trafficking within sciatic nerves of MFN2 T105M mice, suggesting a therapeutic approach for CMT2A and other diseases of impaired neuronal mitochondrial dynamism and/or trafficking. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29674596" 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="#15" class="mim-tip-reference" title="Franco, A., Kitsis, R. N., Fleischer, J. A., Gavathiotis, E., Kornfeld, O. S., Gong, G., Biris, N., Benz, A., Qvit, N., Donnelly, S. K., Chen, Y., Mennerick, S., Hodgson, L., Mochly-Rosen, D., Dorn, G. W., II. <strong>Correcting mitochondrial fusion by manipulating mitofusin conformations.</strong> Nature 540: 74-79, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27775718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27775718</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27775718[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/10.1038/nature20156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27775718">Franco et al. (2016)</a> showed that mitofusins adopt either a fusion-constrained or a fusion-permissive molecular conformation, directed by specific intramolecular binding interactions, and demonstrated that mitofusin-dependent mitochondrial fusion can be regulated in mouse cells by targeting these conformational transitions. On the basis of this model, <a href="#15" class="mim-tip-reference" title="Franco, A., Kitsis, R. N., Fleischer, J. A., Gavathiotis, E., Kornfeld, O. S., Gong, G., Biris, N., Benz, A., Qvit, N., Donnelly, S. K., Chen, Y., Mennerick, S., Hodgson, L., Mochly-Rosen, D., Dorn, G. W., II. <strong>Correcting mitochondrial fusion by manipulating mitofusin conformations.</strong> Nature 540: 74-79, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27775718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27775718</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27775718[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/10.1038/nature20156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27775718">Franco et al. (2016)</a> engineered a cell-permeant minipeptide to destabilize the fusion-constrained conformation of mitofusin and promote the fusion-permissive conformation, reversing mitochondrial abnormalities in cultured fibroblasts and neurons that harbor CMT2A-associated genetic defects. <a href="#15" class="mim-tip-reference" title="Franco, A., Kitsis, R. N., Fleischer, J. A., Gavathiotis, E., Kornfeld, O. S., Gong, G., Biris, N., Benz, A., Qvit, N., Donnelly, S. K., Chen, Y., Mennerick, S., Hodgson, L., Mochly-Rosen, D., Dorn, G. W., II. <strong>Correcting mitochondrial fusion by manipulating mitofusin conformations.</strong> Nature 540: 74-79, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27775718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27775718</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27775718[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/10.1038/nature20156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27775718">Franco et al. (2016)</a> concluded that the relationship between the conformational plasticity of mitofusin-2 and mitochondrial dynamism revealed a central mechanism that regulates mitochondrial fusion, the manipulation of which can correct mitochondrial pathology triggered by defective or imbalanced mitochondrial dynamics. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27775718" 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="#17" class="mim-tip-reference" title="Gong, G., Song, M., Csordas, G., Kelly, D. P., Matkovich, S. J., Dorn, G. W., II. <strong>Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice.</strong> Science 350: aad2459, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26785495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26785495</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26785495[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aad2459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26785495">Gong et al. (2015)</a> found that Pink1 (<a href="/entry/608309">608309</a>)-Mfn2-parkin (<a href="/entry/602544">602544</a>)-mediated mitophagy directs the change in mitochondrial substrate preference in developing mouse hearts from carbohydrates to fatty acids. A Mfn2 mutant lacking Pink1 phosphorylation sites necessary for parkin binding (Mfn2 AA) inhibited mitochondrial parkin translocation, suppressing mitophagy without impairing mitochondrial fusion. Cardiac Parkin deletion or expression of Mfn2 AA from birth, but not after weaning, prevented postnatal mitochondrial maturation essential to survival. Five-week-old Mfn2 AA hearts retained a fetal mitochondrial transcriptional signature without normal increases in fatty acid metabolism and mitochondrial biogenesis genes. Myocardial fatty acylcarnitine levels and cardiomyocyte respiration induced by palmitoylcarnitine were concordantly depressed. Thus, instead of transcriptional reprogramming, fetal cardiomyocyte mitochondria undergo perinatal parkin-mediated mitophagy and replacement by mature adult mitochondria. <a href="#17" class="mim-tip-reference" title="Gong, G., Song, M., Csordas, G., Kelly, D. P., Matkovich, S. J., Dorn, G. W., II. <strong>Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice.</strong> Science 350: aad2459, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26785495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26785495</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26785495[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aad2459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26785495">Gong et al. (2015)</a> concluded that mitophagic mitochondrial removal underlies developmental cardiomyocyte mitochondrial plasticity and metabolic transitioning of perinatal hearts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26785495" 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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In affected members of several families with autosomal dominant Charcot-Marie-Tooth disease-2A2A (CMT2A2A; <a href="/entry/609260">609260</a>), <a href="#42" class="mim-tip-reference" title="Zuchner, S., Mersiyanova, I. V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali, E. L., Zappia, M., Nelis, E., Patitucci, A., Senderek, J., Parman, Y., Evgrafov, O., and 10 others. <strong>Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.</strong> Nature Genet. 36: 449-451, 2004. Note: Erratum: Nature Genet. 36: 660 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15064763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15064763</a>] [<a href="https://doi.org/10.1038/ng1341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15064763">Zuchner et al. (2004)</a> identified heterozygous mutations in the MFN2 gene (<a href="#0001">608507.0001</a>-<a href="#0006">608507.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15064763" 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="#22" class="mim-tip-reference" title="Kijima, K., Numakura, C., Izumino, H., Umetsu, K., Nezu, A., Shiiki, T., Ogawa, M., Ishizaki, Y., Kitamura, T., Shozawa, Y., Hayasaka, K. <strong>Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A.</strong> Hum. Genet. 116: 23-27, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15549395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15549395</a>] [<a href="https://doi.org/10.1007/s00439-004-1199-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15549395">Kijima et al. (2005)</a> studied the MFN2 gene in 81 Japanese patients with axonal or unclassified CMT and detected 7 mutations in 7 unrelated patients. Six mutations were novel, and 1 was a de novo mutation. Most mutations were located within or immediately upstream of the GTPase domain or within 2 coiled-coil domains critical for mitochondrial targeting of MFN2. <a href="#22" class="mim-tip-reference" title="Kijima, K., Numakura, C., Izumino, H., Umetsu, K., Nezu, A., Shiiki, T., Ogawa, M., Ishizaki, Y., Kitamura, T., Shozawa, Y., Hayasaka, K. <strong>Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A.</strong> Hum. Genet. 116: 23-27, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15549395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15549395</a>] [<a href="https://doi.org/10.1007/s00439-004-1199-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15549395">Kijima et al. (2005)</a> stated that formation of the mitochondrial network would be required to maintain the functional peripheral nerve axon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15549395" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 6 unrelated families with hereditary motor and sensory neuropathy with optic atrophy (HMSN6A; <a href="/entry/601152">601152</a>), <a href="#41" class="mim-tip-reference" title="Zuchner, S., De Jonghe, P., Jordanova, A., Claeys, K. G., Guergueltcheva, V., Cherninkova, S., Hamilton, S. R., Van Stavern, G., Krajewski, K. M., Stajich, J., Tournev, I., Verhoeven, K., Langerhorst, C. T., de Visser, M., Baas, F., Bird, T., Timmerman, V., Shy, M., Vance, J. M. <strong>Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2.</strong> Ann. Neurol. 59: 276-281, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16437557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16437557</a>] [<a href="https://doi.org/10.1002/ana.20797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16437557">Zuchner et al. (2006)</a> identified 6 different heterozygous mutations in the MFN2 gene (see, e.g., <a href="#0009">608507.0009</a>-<a href="/entry/608607#0012">608607.0012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16437557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Chung, K. W., Kim, S. B., Park, K. D., Choi, K. G., Lee, J. H., Eun, H. W., Suh, J. S., Hwang, J. H., Kim, W. K., Seo, B. C., Kim, S. H., Son, I. H., Kim, S. M., Sunwoo, I. N., Choi, B. O. <strong>Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations.</strong> Brain 129: 2103-2118, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16835246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16835246</a>] [<a href="https://doi.org/10.1093/brain/awl174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16835246">Chung et al. (2006)</a> identified 10 pathogenic MFN2 mutations (see, e.g., <a href="#0004">608507.0004</a>; <a href="#0009">608507.0009</a>; <a href="#0011">608507.0011</a>) in 26 patients from 15 (24.2%) of 62 Korean families with CMT2A2 or HMSN VI. There were 2 main groups of patients, including those with early onset before 10 years and those with late onset after age 10 years. Those with early onset had a severe disorder, often with scoliosis and contractures, whereas those with later onset had a milder disorder and a higher frequency of unusual findings such as tremor, pain, and hearing loss. The severity of the disorder tended to be the same within families, suggesting a genotype/phenotype correlation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16835246" 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 fibroblasts derived from CMT2A2 patients with MFN2 mutations (see, e.g., R94Q, <a href="#0001">608507.0001</a>), <a href="#18" class="mim-tip-reference" title="Guillet, V., Gueguen, N., Verny, C., Ferre, M., Homedan, C., Loiseau, D., Procaccio, V., Amati-Bonneau, P., Bonneau, D., Reynier, P., Chevrollier, A. <strong>Adenine nucleotide translocase is involved in a mitochondrial coupling defect in MFN2-related Charcot-Marie-Tooth type 2A disease.</strong> Neurogenetics 11: 127-133, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19618221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19618221</a>] [<a href="https://doi.org/10.1007/s10048-009-0207-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19618221">Guillet et al. (2010)</a> found an uncoupling of mitochondrial oxygen consumption and decreased efficiency of oxygen utilization, but normal ATP production. Normal ATP production was maintained by an increased respiration rate, mainly involving complex II proteins. Mutant fibroblasts also showed overexpression and increased activity of ANT3 (SLC25A6; <a href="/entry/300151">300151</a>), which was believed to result in reduced efficiency of oxidative phosphorylation. The findings suggested that MFN2 plays a role in controlling ATP/ADP exchange in mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19618221" 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="#5" class="mim-tip-reference" title="Calvo, J., Funalot, B., Ouvrier, R. A., Lazaro, L., Toutain, A., De Mas, P., Bouche, P., Gilbert-Dussardier, B., Arne-Bes, M.-C., Carriere, J.-P., Journel, H., Minot-Myhie, M.-C., Guillou, C., Ghorab, K., Magy, L., Sturtz, F., Vallat, J.-M., Magdelaine, C. <strong>Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations.</strong> Arch. Neurol. 66: 1511-1516, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20008656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20008656</a>] [<a href="https://doi.org/10.1001/archneurol.2009.284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20008656">Calvo et al. (2009)</a> identified 20 different missense mutations, including 10 novel mutations, in the MFN2 gene in 20 of 150 probands with CMT and a nerve conduction velocity (NCV) of 25 m/s or greater. Eighteen of the patients had been previously reported. The mutation frequency in CMT2 was 17.8% (19 of 107 patients) and in CMT1 was 2.3% (1 of 43). Four patients had proven de novo mutations, 8 families had autosomal dominant inheritance, and 3 had autosomal recessive inheritance; the remaining 5 patients were sporadic cases with heterozygous mutations. The phenotypes varied from mild forms to early-onset severe forms, and additional features, such as pyramidal signs or vasomotor dysfunction, were encountered in 8 patients (32%). The study indicated that MFN2 mutations are a frequent cause of CMT2, with variable severity and either dominant or recessive inheritance. <a href="#5" class="mim-tip-reference" title="Calvo, J., Funalot, B., Ouvrier, R. A., Lazaro, L., Toutain, A., De Mas, P., Bouche, P., Gilbert-Dussardier, B., Arne-Bes, M.-C., Carriere, J.-P., Journel, H., Minot-Myhie, M.-C., Guillou, C., Ghorab, K., Magy, L., Sturtz, F., Vallat, J.-M., Magdelaine, C. <strong>Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations.</strong> Arch. Neurol. 66: 1511-1516, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20008656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20008656</a>] [<a href="https://doi.org/10.1001/archneurol.2009.284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20008656">Calvo et al. (2009)</a> suggested that testing for mutations in MFN2 showed be a first-line analysis in axonal CMT regardless of the mode of inheritance or the severity of the peripheral neuropathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20008656" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Casasnovas, C., Banchs, I., Cassereau, J., Gueguen, N., Chevrollier, A., Martinez-Matos, J. A., Bonneau, D., Volpini, V. <strong>Phenotypic spectrum of MFN2 mutations in the Spanish population.</strong> J. Med. Genet. 47: 249-256, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19889647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19889647</a>] [<a href="https://doi.org/10.1136/jmg.2009.072488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19889647">Casasnovas et al. (2010)</a> identified 9 different heterozygous MFN2 mutations, including 4 novel mutations, in 24 patients from 14 different Spanish families with CMT2A2. Six (42.8%) of 14 families carried the same mutation (R468H; <a href="#0015">608507.0015</a>). Overall, MFN2 mutations were identified in 16% of the total cohort of 85 Spanish families with axonal CMT, and <a href="#8" class="mim-tip-reference" title="Casasnovas, C., Banchs, I., Cassereau, J., Gueguen, N., Chevrollier, A., Martinez-Matos, J. A., Bonneau, D., Volpini, V. <strong>Phenotypic spectrum of MFN2 mutations in the Spanish population.</strong> J. Med. Genet. 47: 249-256, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19889647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19889647</a>] [<a href="https://doi.org/10.1136/jmg.2009.072488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19889647">Casasnovas et al. (2010)</a> concluded that MFN2 is the most frequent cause of axonal CMT in this population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19889647" 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 British sibs with autosomal recessive inheritance of severe early-onset Charcot-Marie-Tooth disease-2A2B (CMT2A2B; <a href="/entry/617087">617087</a>), <a href="#31" class="mim-tip-reference" title="Polke, J. M., Laura, M., Pareyson, D., Taroni, F., Milani, M., Bergamin, G., Gibbons, V. S., Houlden, H., Chamley, S. C., Blake, J., DeVile, C., Sandford, R., Sweeney, M. G., Davis, M. B., Reilly, M. M. <strong>Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations.</strong> Neurology 77: 168-173, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21715711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21715711</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182242d4d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21715711">Polke et al. (2011)</a> identified compound heterozygosity for 2 mutations in the MFN2 gene (<a href="#0017">608507.0017</a>-<a href="#0018">608507.0018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21715711" 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="#23" class="mim-tip-reference" title="Larrea, D., Pera, M., Gonnelli, A., Quintana-Cabrera, R., Akman, H. I., Guardia-Laguarta, C., Velasco, K. R., Area-Gomez, E., Dal Bello, F., De Stefani, D., Horvath, R., Shy, M. E., Schon, E. A., giacomello, M. <strong>MFN2 mutations in Charcot-Marie-Tooth disease alter mitochondria-associated ER membrane function but do not impair bioenergetics.</strong> Hum. Molec. Genet. 28: 1782-1800, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30649465/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30649465</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30649465[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddz008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30649465">Larrea et al. (2019)</a> evaluated mitochondrial bioenergetics and mitochondrial-associated ER membrane (MAM) function in fibroblasts from 3 individuals with CMT2A2B and mutations in MFN2. The first individual (P1) was a 32-year-old woman with an R364W mutation (<a href="#0011">608507.0011</a>) and a severe presentation, including onset of mobility and balance issues at age 2 years and 7 months. The second individual (P2) was a 62-year-old man with an M376V mutation who had mild clinical features and presented with weakness at age 11 years. The third individual (P3) was a 34-year-old woman with a W740S mutation (<a href="#0002">608507.0002</a>) with a mild clinical presentation. Gene expression studies showed that steady-state levels of MFN2 mRNA were approximately 2-fold higher in patient fibroblasts compared to controls, and that mutant and wildtype alleles were expressed at essentially the same steady-state level in all 3 patient fibroblast lines. MFN2 protein levels were not different between patient and control fibroblasts. Mitochondrial morphology studies showed no difference between control and mutant mitochondrial perimeter or surface area, but patient cells showed a lower degree of physical association between the mitochondria and ER. An assessment of several measures of MAM function showed that, compared to controls, P3 fibroblasts had reduced serine incorporation in phosphatidylserine and phosphatidylethanolamine; P1 and P2 fibroblasts had increased cholesteryl ester synthesis; and P1 fibroblasts had significantly increased lipid droplets. Evaluation of calcium homeostasis showed only moderate and variable differences between patients and controls. Additionally, bioenergetic function, as measured by oxygen consumption studies, was not impaired in patient versus control cells. <a href="#23" class="mim-tip-reference" title="Larrea, D., Pera, M., Gonnelli, A., Quintana-Cabrera, R., Akman, H. I., Guardia-Laguarta, C., Velasco, K. R., Area-Gomez, E., Dal Bello, F., De Stefani, D., Horvath, R., Shy, M. E., Schon, E. A., giacomello, M. <strong>MFN2 mutations in Charcot-Marie-Tooth disease alter mitochondria-associated ER membrane function but do not impair bioenergetics.</strong> Hum. Molec. Genet. 28: 1782-1800, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30649465/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30649465</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30649465[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddz008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30649465">Larrea et al. (2019)</a> concluded that differences in the characteristics of mitochondrial-ER communication resulting from individual MFN2 mutations may have different effects on MAM function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30649465" 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="#30" class="mim-tip-reference" title="Pipis, M. Feely, S. M. E., Polke, J. M., Skorupinska, M., Perez, L., Shy, R. R., Laura, M., Morrow, J. M., Moroni, I., Pisciotta, C., Taroni, F., Vujovic, D., and 22 others. <strong>Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study.</strong> Brain 143: 3589-3602, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33415332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33415332</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33415332[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awaa323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33415332">Pipis et al. (2020)</a> evaluated clinical and molecular findings in 196 individuals with CMT2A2A and CMT2A2B in a large multicenter prospective cohort study. One hundred and seventy-nine individuals from 133 families had dominant mutations, and 17 patients from 13 families had compound heterozygous (16 patients) or homozygous mutations (1 patient), in MFN2. The majority of mutations occurred in the dynamin-GTPase domain. Genetic variants at certain amino acid positions, including arg94, arg104, ser249, and trp740, were always pathogenic, with no evidence of reduced penetrance or variable expressivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33415332" 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>Multiple Symmetric Lipomatosis With or Without Axonal Peripheral Neuropathy</em></strong></p><p>
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In a 33-year-old woman (CMT40) with multiple symmetric lipomatosis (MSL; <a href="/entry/151800">151800</a>) and early-onset severe axonal peripheral neuropathy, <a href="#27" class="mim-tip-reference" title="Nicholson, G. A., Magdelaine, C., Zhu, D., Grew, S., Ryan, M. M., Sturtz, F., Vallat, J.-M., Ouvrier, R. A. <strong>Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations.</strong> Neurology 70: 1678-1681, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18458227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18458227</a>] [<a href="https://doi.org/10.1212/01.wnl.0000311275.89032.22" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18458227">Nicholson et al. (2008)</a> identified a homozygous missense mutation in the MFN2 gene (R707W; <a href="#0013">608507.0013</a>). Each parent was heterozygous for the mutation and showed mild features of a peripheral neuropathy, although they were not diagnosed with Charcot-Marie-Tooth disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18458227" 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, born of consanguineous Irish parents, with MSL and late-onset axonal peripheral neuropathy, <a href="#36" class="mim-tip-reference" title="Sawyer, S. L., Cheuk-Him Ng, A., Innes, A. M., Wagner, J. D., Dyment, D. A., Tetreault, M., Care4Rare Canada Consortium, Majewski, J., Boycott, K. M., Screaton, R. A., Nicholson, G. <strong>Homozygous mutations in MFN2 cause multiple symmetric lipomatosis associated with neuropathy.</strong> Hum. Molec. Genet. 24: 5109-5114, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26085578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26085578</a>] [<a href="https://doi.org/10.1093/hmg/ddv229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26085578">Sawyer et al. (2015)</a> identified a homozygous R707W mutation in the MFN2 gene. The mutation, which was found by whole-exome sequencing, was not present in their unaffected sibs. In vitro expression studies in MFN2-null cells showed that the R707W mutant had a reduced capacity to tubulate mitochondria. In addition, mitochondria in mutant cells were prone to aggregation, were defective in forming homo-oligomers, and formed smaller oligomeric complexes compared to wildtype MFN2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26085578" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Carr, A. S, Polke, J. M., Wilson, J., Pelayo-Negro, A. L., Laura, M., Nanji, T., Holt, J., Vaughan, J., Rankin, J., Sweeney, M. G., Blake, J., Houlden, H., Reilly, M. M. <strong>MFN2 deletion of exons 7 and 8: founder mutation in the UK population.</strong> J. Peripher. Nerv. Syst. 20: 67-71, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26114802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26114802</a>] [<a href="https://doi.org/10.1111/jns.12117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26114802">Carr et al. (2015)</a> reported a 44-year-old patient (family 4) of UK origin with MSL and early-onset axonal peripheral neuropathy associated with compound heterozygous mutations in the MFN2 gene: an exon 7/8 deletion (<a href="#0018">608507.0018</a>) and R707W. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26114802" 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 3 patients (P2, P3, and P4) from 2 unrelated European families with MSL, <a href="#33" class="mim-tip-reference" title="Rocha, N., Bulger, D. A., Frontini, A., Titheradge, H., Gribsholt, S. B., Knox, R., Page, M., Harris, J., Payne, F., Adams, C., Sleigh, A., Crawford, J., and 19 others. <strong>Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression.</strong> eLife 6: e23813, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28414270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28414270</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28414270[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.7554/eLife.23813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28414270">Rocha et al. (2017)</a> identified a homozygous R707W mutation in the MFN2 gene. Another patient with the disorder (P1) was compound heterozygous for R707W and arg343del (<a href="#0023">608507.0023</a>). The mutations, which were found by exome sequencing or direct Sanger sequencing, segregated with the disorder in the families from whom parental DNA was available for study. Studies of abnormal adipose tissue showed hyperplasia of UCP1 (<a href="/entry/113730">113730</a>)-negative unilocular adipocytes and proliferation of round, enlarged mitochondria with fragmented cristae. Transcriptome analysis of adipose tissue showed perturbation of gene expression related to mitochondrial dysfunction and oxidative phosphorylation. There was also activation of genes related to cellular stress response pathways, including oxidative stress and unfolded protein response pathways, and upregulation of signatures related to tissue proliferation and survival. Examination of gene expression patterns identified the overgrown adipose tissue as white adipose tissue. In contrast, patient fibroblasts showed normal MFN2 expression and appropriate mitochondrial localization with normal mitochondria. These findings suggested that the abnormalities resulting from MFN2 mutations are tissue-specific. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28414270" 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 6 patients from 5 families of French or Portuguese descent with MSL, <a href="#6" class="mim-tip-reference" title="Capel, E., Vatier, C., Cervera, P., Stojkovic, T., Disse, E., Cottereau, A.-S., Auclair, M., Verpont, M.-C., Mosbah, H., Gourdy, P., Barraud, S., Miquel, A., and 12 others. <strong>MFN2-associated lipomatosis: clinical spectrum and impact on adipose tissue.</strong> J. Clin. Lipid. 12: 1420-1435, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30158064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30158064</a>] [<a href="https://doi.org/10.1016/j.jacl.2018.07.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30158064">Capel et al. (2018)</a> identified a homozygous R707W mutation in the MFN2 gene. The patients were ascertained from a cohort of 66 individuals with altered fat distribution and lipomas who underwent sequencing of the MFN2 gene. Patient-derived lipomatous adipose tissue showed weak expression of the brown fat marker UCP1, and increased expression of thermogenic markers CITED1 (<a href="/entry/300149">300149</a>) and FGF21 (<a href="/entry/609436">609436</a>). Ultrastructural studies showed enlargement of the cytoplasmic ring of adipocytes and increased numbers of enlarged mitochondria with disorganized cristae or double membrane structures, suggestive of mitophagy. Gene expression studies of lipomatous tissue showed normal MFN2 expression and decreased expression of leptin and adiponectin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30158064" 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>Associations Pending Confirmation</em></strong></p><p>
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Using data from the platelet RNA and expression-1 (PRAX1) study, previous genomewide association studies (GWAS) of cardiovascular disease, and platelet-specific gene and allele-specific expression analysis in platelets from 154 normal individuals, <a href="#37" class="mim-tip-reference" title="Simon, L. M., Chen, E. S., Edelstein, L. C., Kong, X., Bhatlekar, S., Rigoutsos, I., Bray, P. F., Shaw, C. A. <strong>Integrative multi-omic analysis of human platelet eQTLs reveals alternative start site in mitofusin 2.</strong> Am. J. Hum. Genet. 98: 883-897, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27132591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27132591</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27132591[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.03.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27132591">Simon et al. (2016)</a> identified <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1474868;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1474868</a> in the MFN2 gene as a possible functional variant. This SNP drives expression of a platelet-specific alternative 5-prime start site, located in an unannotated human platelet-expressed exon termed 'exon 2b.' A noncoding variant in linkage disequilibrium with <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1474868;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1474868</a>, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3766744;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3766744</a>, was identified as a regulator of MFN2 transcriptional activity, and platelet count and MFN2 expression were associated with allele dosage of the latter variant. The study linked <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1474868;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1474868</a> to a platelet-specific regulatory role for MFN2 and provided some evidence for the hypothesis that increased platelet count may be a risk factor for cardiovascular disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27132591" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Chen, H., Detmer, S. A., Ewald, A. J., Griffin, E. E., Fraser, S. E., Chan, D. C. <strong>Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development.</strong> J. Cell Biol. 160: 189-200, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12527753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12527753</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12527753[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/10.1083/jcb.200211046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12527753">Chen et al. (2003)</a> found that both Mfn1- and Mfn2-deficient mice died in midgestation. Whereas Mfn2 mutant embryos showed disruption of the placental trophoblast giant cell layer, Mfn1-deficient giant cells were normal. Embryonic fibroblasts lacking Mfn displayed fragmented mitochondria due to severe reduction in mitochondrial fusion. Mfn1 and Mfn2 formed homotypic and heterotypic complexes, and rescue of mutant cells indicated that the homotypic complexes were functional for fusion. A subset of mitochondria in mutant cells also lost membrane potential. The authors concluded that Mfn1 and Mfn2 have both redundant and distinct functions and act in 3 separate molecular complexes to promote mitochondrial fusion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12527753" 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="#14" class="mim-tip-reference" title="Detmer, S. A., Vande Velde, C., Cleveland, D. W., Chan, D. C. <strong>Hindlimb gait defects due to motor axon loss and reduced distal muscles in a transgenic mouse model of Charcot-Marie-Tooth type 2A.</strong> Hum. Molec. Genet. 17: 367-375, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17959936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17959936</a>] [<a href="https://doi.org/10.1093/hmg/ddm314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17959936">Detmer et al. (2008)</a> generated transgenic mice expressing a pathogenic Mfn2 T105M mutation in peripheral motor neurons. Mutant mice developed key clinical features of CMT2A in a dose-dependent manner. Homozygous mice had a severe gait defect from birth due to an inability to dorsiflex the hindpaws, and they consequently dragged their hindpaws while walking and supported themselves on the hind knuckles, rather than the soles. Anterior calf muscles showed severe atrophy. There was decreased penetrance of the defects as well as lack of progression. Histologic studies showed reduced numbers of motor axons in the motor roots and improper mitochondrial distribution with tight clusters of mitochondria within axons. Homozygous mice had drastically short tails that were deformed, whereas heterozygous mice had shorter tails with mild to moderate bony kinks or thickening. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17959936" 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="#16" class="mim-tip-reference" title="Fyfe, J. C., Al-Tamimi, R. A., Liu, J., Schaffer, A. A., Agarwala, R., Henthorn, P. S. <strong>A novel mitofusin 2 mutation causes canine fetal-onset neuroaxonal dystrophy.</strong> Neurogenetics 12: 223-232, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21643798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21643798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21643798[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/10.1007/s10048-011-0285-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21643798">Fyfe et al. (2011)</a> used genomewide linkage analysis followed by candidate gene sequencing to identify a homozygous 3-bp deletion in the canine Mfn2 gene as causative of a severe autosomal recessive form of fetal-onset neuroaxonal dystrophy. The in-frame 3-bp deletion was predicted to result in the deletion of a conserved glu539 residue. Mutant mRNA was expressed, but mutant protein was nearly undetectable on Western blot analysis of dog tissues. Immunohistochemical studies of normal pup brainstem showed robust granular cytoplasmic staining of Mfn2 in cerebellar Purkinje cells, deep cerebellar nuclei, and most large neurons in identified nuclei. The phenotype was characterized by death at birth due to respiratory failure. Affected fetuses had swollen axons/spheroids throughout the extrapyramidal motor system of the brainstem, spinal cord, and peripheral nerves, as well as cerebellar hypoplasia. Axonal swelling was composed of membrane-bound fragments of variably degenerated mitochondria and other tubulofilamentous material. The phenotype was reminiscent of human neuroaxonal dystrophy (<a href="/entry/256600">256600</a>) caused by mutation in the PLA2G6 gene (<a href="/entry/603604">603604</a>); however, brain iron accumulation was not observed in canines with the Mfn2 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21643798" 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 affected members of a Japanese kindred (family 693) with autosomal dominant Charcot-Marie-Tooth disease-2A2A (CMT2A2A; <a href="/entry/609260">609260</a>) originally reported by <a href="#34" class="mim-tip-reference" title="Saito, M., Hayashi, Y., Suzuki, T., Tanaka, H., Hozumi, I., Tsuji, S. <strong>Linkage mapping of the gene for Charcot-Marie-Tooth disease type 2 to chromosome 1p (CMT2A) and the clinical features of CMT2A.</strong> Neurology 49: 1630-1635, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9409358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9409358</a>] [<a href="https://doi.org/10.1212/wnl.49.6.1630" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9409358">Saito et al. (1997)</a> as well as in a Russian kindred with CMT2A2A, <a href="#42" class="mim-tip-reference" title="Zuchner, S., Mersiyanova, I. V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali, E. L., Zappia, M., Nelis, E., Patitucci, A., Senderek, J., Parman, Y., Evgrafov, O., and 10 others. <strong>Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.</strong> Nature Genet. 36: 449-451, 2004. Note: Erratum: Nature Genet. 36: 660 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15064763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15064763</a>] [<a href="https://doi.org/10.1038/ng1341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15064763">Zuchner et al. (2004)</a> identified a heterozygous 281G-A transition in the MFN2 gene, resulting in an arg94-to-gln (R94Q) substitution in the predicted beginning of the GTPase domain of the protein. Age at disease onset in the 2 kindreds ranged from 3 to 17 years. A different mutation affecting the same codon (R94W; <a href="#0009">608507.0009</a>) was identified in another patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15064763+9409358" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Casasnovas, C., Banchs, I., Cassereau, J., Gueguen, N., Chevrollier, A., Martinez-Matos, J. A., Bonneau, D., Volpini, V. <strong>Phenotypic spectrum of MFN2 mutations in the Spanish population.</strong> J. Med. Genet. 47: 249-256, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19889647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19889647</a>] [<a href="https://doi.org/10.1136/jmg.2009.072488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19889647">Casasnovas et al. (2010)</a> identified a heterozygous R94Q mutation in affected members of a Spanish family with early-onset severe CMT2A2A and optic atrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19889647" 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">rs28940292 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940292;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=rs28940292" 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=rs28940292" 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=RCV000002357 OR RCV000197403 OR RCV000235811 OR RCV000763240 OR RCV000857112 OR RCV001001747 OR RCV002426480 OR RCV002444413" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002357, RCV000197403, RCV000235811, RCV000763240, RCV000857112, RCV001001747, RCV002426480, RCV002444413" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002357...</a>
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<p>In affected members of a family with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; <a href="/entry/609260">609260</a>) originally reported by <a href="#2" class="mim-tip-reference" title="Ben Othmane, K., Middleton, L. T., Loprest, L. J., Wilkinson, K. M., Lennon, F., Rozear, M. P., Stajich, J. M., Gaskell, P. C., Roses, A. D., Pericak-Vance, M. A., Vance, J. M. <strong>Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity.</strong> Genomics 17: 370-375, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8406488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8406488</a>] [<a href="https://doi.org/10.1006/geno.1993.1334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8406488">Ben Othmane et al. (1993)</a>, <a href="#42" class="mim-tip-reference" title="Zuchner, S., Mersiyanova, I. V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali, E. L., Zappia, M., Nelis, E., Patitucci, A., Senderek, J., Parman, Y., Evgrafov, O., and 10 others. <strong>Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.</strong> Nature Genet. 36: 449-451, 2004. Note: Erratum: Nature Genet. 36: 660 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15064763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15064763</a>] [<a href="https://doi.org/10.1038/ng1341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15064763">Zuchner et al. (2004)</a> identified a heterozygous 2219G-C transversion in the MFN2 gene, resulting in a trp740-to-ser (W740S) substitution. Age at disease onset ranged from 5 to 52 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15064763+8406488" 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 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28940293 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940293;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/rs28940293?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=rs28940293" 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=rs28940293" 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=RCV000002358 OR RCV000200837 OR RCV000653847" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002358, RCV000200837, RCV000653847" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002358...</a>
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<p>In affected members of a family with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; <a href="/entry/609260">609260</a>) originally reported by <a href="#28" class="mim-tip-reference" title="Pericak-Vance, M. A., Speer, M. C., Lennon, F., West, S. G., Menold, M. M., Stajich, J. M., Wolpert, C. M., Slotterbeck, B. D., Saito, M., Tim, R. W., Rozear, M. P., Middleton, L. T., Tsuji, S., Vance, J. M. <strong>Confirmation of a second locus for CMT2 and evidence for additional genetic heterogeneity.</strong> Neurogenetics 1: 89-93, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10732809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10732809</a>] [<a href="https://doi.org/10.1007/s100480050013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10732809">Pericak-Vance et al. (1997)</a>, <a href="#42" class="mim-tip-reference" title="Zuchner, S., Mersiyanova, I. V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali, E. L., Zappia, M., Nelis, E., Patitucci, A., Senderek, J., Parman, Y., Evgrafov, O., and 10 others. <strong>Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.</strong> Nature Genet. 36: 449-451, 2004. Note: Erratum: Nature Genet. 36: 660 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15064763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15064763</a>] [<a href="https://doi.org/10.1038/ng1341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15064763">Zuchner et al. (2004)</a> identified a heterozygous 227T-C transition in the MFN2 gene, resulting in a leu76-to-pro (L76P) substitution. Age at disease onset ranged from 7 to 44 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15064763+10732809" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28940294 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940294;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/rs28940294?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=rs28940294" 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=rs28940294" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a family with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; <a href="/entry/609260">609260</a>) originally reported by <a href="#28" class="mim-tip-reference" title="Pericak-Vance, M. A., Speer, M. C., Lennon, F., West, S. G., Menold, M. M., Stajich, J. M., Wolpert, C. M., Slotterbeck, B. D., Saito, M., Tim, R. W., Rozear, M. P., Middleton, L. T., Tsuji, S., Vance, J. M. <strong>Confirmation of a second locus for CMT2 and evidence for additional genetic heterogeneity.</strong> Neurogenetics 1: 89-93, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10732809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10732809</a>] [<a href="https://doi.org/10.1007/s100480050013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10732809">Pericak-Vance et al. (1997)</a>, <a href="#42" class="mim-tip-reference" title="Zuchner, S., Mersiyanova, I. V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali, E. L., Zappia, M., Nelis, E., Patitucci, A., Senderek, J., Parman, Y., Evgrafov, O., and 10 others. <strong>Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.</strong> Nature Genet. 36: 449-451, 2004. Note: Erratum: Nature Genet. 36: 660 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15064763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15064763</a>] [<a href="https://doi.org/10.1038/ng1341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15064763">Zuchner et al. (2004)</a> identified a heterozygous 839G-A transition in the MFN2 gene, resulting in an arg280-to-his (R280H) substitution. Age at disease onset ranged from 11 to 35 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15064763+10732809" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Chung, K. W., Kim, S. B., Park, K. D., Choi, K. G., Lee, J. H., Eun, H. W., Suh, J. S., Hwang, J. H., Kim, W. K., Seo, B. C., Kim, S. H., Son, I. H., Kim, S. M., Sunwoo, I. N., Choi, B. O. <strong>Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations.</strong> Brain 129: 2103-2118, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16835246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16835246</a>] [<a href="https://doi.org/10.1093/brain/awl174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16835246">Chung et al. (2006)</a> reported a large multigenerational Korean family with late-onset CMT2A2A carrying a heterozygous R280H mutation. Onset ranged between 11 and 42 years, and affected individuals had mild muscle weakness and atrophy. Associated but variable features included pain, tremor, dysarthria, extensor plantar responses, and migraine. One patient had sensorineural hearing loss. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16835246" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A</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">rs28940295 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940295;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=rs28940295" 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=rs28940295" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of an Italian family with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; <a href="/entry/609260">609260</a>) originally reported by <a href="#25" class="mim-tip-reference" title="Muglia, M., Zappia, M., Timmerman, V., Valentino, P., Gabriele, A. L., Conforti, F. L., De Jonghe, P., Ragno, M., Mazzei, R., Sabatelli, M., Nicoletti, G., Patitucci, A. M., Oliveri, R. L., Bono, F., Gambardella, A., Quattrone, A. <strong>Clinical and genetic study of a large Charcot-Marie-Tooth type 2A family from southern Italy.</strong> Neurology 56: 100-103, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11148244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11148244</a>] [<a href="https://doi.org/10.1212/wnl.56.1.100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11148244">Muglia et al. (2001)</a>, <a href="#42" class="mim-tip-reference" title="Zuchner, S., Mersiyanova, I. V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali, E. L., Zappia, M., Nelis, E., Patitucci, A., Senderek, J., Parman, Y., Evgrafov, O., and 10 others. <strong>Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.</strong> Nature Genet. 36: 449-451, 2004. Note: Erratum: Nature Genet. 36: 660 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15064763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15064763</a>] [<a href="https://doi.org/10.1038/ng1341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15064763">Zuchner et al. (2004)</a> identified a heterozygous 751C-G transversion in the MFN2 gene, resulting in a pro251-to-ala (P251A) substitution. Age at disease onset ranged from 8 to 50 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11148244+15064763" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28940296 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940296;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/rs28940296?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=rs28940296" 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=rs28940296" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a Turkish family with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; <a href="/entry/609260">609260</a>), <a href="#42" class="mim-tip-reference" title="Zuchner, S., Mersiyanova, I. V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali, E. L., Zappia, M., Nelis, E., Patitucci, A., Senderek, J., Parman, Y., Evgrafov, O., and 10 others. <strong>Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.</strong> Nature Genet. 36: 449-451, 2004. Note: Erratum: Nature Genet. 36: 660 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15064763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15064763</a>] [<a href="https://doi.org/10.1038/ng1341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15064763">Zuchner et al. (2004)</a> identified a heterozygous c.205G-T transversion in the MFN2 gene, resulting in a val69-to-phe (V69F) substitution. Age at disease onset ranged from 5 to 15 years. The family had previously been reported by <a href="#3" class="mim-tip-reference" title="Bissar-Tadmouri, N., Nelis, E., Zuchner, S., Parman, Y., Deymeer, F., Serdaroglu, P., De Jonghe, P., Van Gerwen, V., Timmerman, V., Schroder, J. M., Battaloglu, E. <strong>Absence of KIF1B mutation in a large Turkish CMT2A family suggests involvement of a second gene.</strong> Neurology 62: 1522-1525, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15136675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15136675</a>] [<a href="https://doi.org/10.1212/01.wnl.0000123253.57555.3a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15136675">Bissar-Tadmouri et al. (2004)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15064763+15136675" 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">rs119103261 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103261;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=rs119103261" 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=rs119103261" 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=RCV000002362 OR RCV000547064 OR RCV005003317" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002362, RCV000547064, RCV005003317" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002362...</a>
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<p>In a Japanese patient with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; <a href="/entry/609260">609260</a>), <a href="#22" class="mim-tip-reference" title="Kijima, K., Numakura, C., Izumino, H., Umetsu, K., Nezu, A., Shiiki, T., Ogawa, M., Ishizaki, Y., Kitamura, T., Shozawa, Y., Hayasaka, K. <strong>Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A.</strong> Hum. Genet. 116: 23-27, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15549395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15549395</a>] [<a href="https://doi.org/10.1007/s00439-004-1199-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15549395">Kijima et al. (2005)</a> identified an apparently de novo missense mutation, lys357 to asn (K357N), resulting from a heterozygous G-to-C transversion at nucleotide 1071 of the MFN2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15549395" 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">rs119103262 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103262;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=rs119103262" 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=rs119103262" 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=RCV000002363 OR RCV000789416 OR RCV001208639" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002363, RCV000789416, RCV001208639" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002363...</a>
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<p>In 11 affected members of a family (CMT66) with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; <a href="/entry/609260">609260</a>), <a href="#40" class="mim-tip-reference" title="Zhu, D., Kennerson, M. L., Walizada, G., Zuchner, S., Vance, J. M., Nicholson, G. A. <strong>Charcot-Marie-Tooth with pyramidal signs is genetically heterogeneous: families with and without MFN2 mutations.</strong> Neurology 65: 496-497, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16087932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16087932</a>] [<a href="https://doi.org/10.1212/01.wnl.0000171345.62270.29" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16087932">Zhu et al. (2005)</a> identified a heterozygous 493C-G transversion in exon 6 of the MFN2 gene, resulting in a his165-to-asp (H165D) substitution in the conserved GTPase domain. The family was previously reported by <a href="#39" class="mim-tip-reference" title="Vucic, S., Kennerson, M., Zhu, D., Miedema, E., Kok, C., Nicholson, G. A. <strong>CMT with pyramidal features.</strong> Neurology 60: 696-699, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12601114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12601114</a>] [<a href="https://doi.org/10.1212/01.wnl.0000048561.61921.71" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12601114">Vucic et al. (2003)</a> as having CMT with pyramidal features. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16087932+12601114" 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 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A</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">rs119103263 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103263;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=rs119103263" 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=rs119103263" 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=RCV000002364 OR RCV000190245 OR RCV000199279 OR RCV000200468 OR RCV000415132 OR RCV001173686 OR RCV003162206 OR RCV004558234 OR RCV004558235" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002364, RCV000190245, RCV000199279, RCV000200468, RCV000415132, RCV001173686, RCV003162206, RCV004558234, RCV004558235" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002364...</a>
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<p>In a patient with early-onset Charcot-Marie-Tooth disease-2A2A (CMT2A2A; <a href="/entry/609260">609260</a>), <a href="#42" class="mim-tip-reference" title="Zuchner, S., Mersiyanova, I. V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali, E. L., Zappia, M., Nelis, E., Patitucci, A., Senderek, J., Parman, Y., Evgrafov, O., and 10 others. <strong>Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.</strong> Nature Genet. 36: 449-451, 2004. Note: Erratum: Nature Genet. 36: 660 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15064763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15064763</a>] [<a href="https://doi.org/10.1038/ng1341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15064763">Zuchner et al. (2004)</a> identified a heterozygous 280C-T transition in exon 4 of the MFN2 gene, resulting in an arg94-to-trp (R94W) substitution. A different mutation affecting the same codon (R94Q; <a href="#0001">608507.0001</a>) was identified in another family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15064763" 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="#41" class="mim-tip-reference" title="Zuchner, S., De Jonghe, P., Jordanova, A., Claeys, K. G., Guergueltcheva, V., Cherninkova, S., Hamilton, S. R., Van Stavern, G., Krajewski, K. M., Stajich, J., Tournev, I., Verhoeven, K., Langerhorst, C. T., de Visser, M., Baas, F., Bird, T., Timmerman, V., Shy, M., Vance, J. M. <strong>Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2.</strong> Ann. Neurol. 59: 276-281, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16437557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16437557</a>] [<a href="https://doi.org/10.1002/ana.20797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16437557">Zuchner et al. (2006)</a> identified a heterozygous R94W mutation in an African American mother and daughter with hereditary motor and sensory neuropathy with optic atrophy (HMSN6A; <a href="/entry/601152">601152</a>). Both patients had early onset of axonal neuropathy, at ages 8 and 3 years, respectively, and late onset of optic atrophy, at ages 50 and 40 years, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16437557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Chung, K. W., Kim, S. B., Park, K. D., Choi, K. G., Lee, J. H., Eun, H. W., Suh, J. S., Hwang, J. H., Kim, W. K., Seo, B. C., Kim, S. H., Son, I. H., Kim, S. M., Sunwoo, I. N., Choi, B. O. <strong>Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations.</strong> Brain 129: 2103-2118, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16835246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16835246</a>] [<a href="https://doi.org/10.1093/brain/awl174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16835246">Chung et al. (2006)</a> identified a heterozygous R94W mutation in 2 Korean families with severe early-onset CMT2A2A and no evidence of optic atrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16835246" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 NEUROPATHY, HEREDITARY MOTOR AND SENSORY, TYPE VIA</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">rs119103264 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103264;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=rs119103264" 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=rs119103264" 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=RCV000002366 OR RCV001253214 OR RCV002426481 OR RCV003482223" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002366, RCV001253214, RCV002426481, RCV003482223" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002366...</a>
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<p>In a woman with hereditary motor and sensory neuropathy type VIA (HMSN6A; <a href="/entry/601152">601152</a>), <a href="#41" class="mim-tip-reference" title="Zuchner, S., De Jonghe, P., Jordanova, A., Claeys, K. G., Guergueltcheva, V., Cherninkova, S., Hamilton, S. R., Van Stavern, G., Krajewski, K. M., Stajich, J., Tournev, I., Verhoeven, K., Langerhorst, C. T., de Visser, M., Baas, F., Bird, T., Timmerman, V., Shy, M., Vance, J. M. <strong>Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2.</strong> Ann. Neurol. 59: 276-281, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16437557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16437557</a>] [<a href="https://doi.org/10.1002/ana.20797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16437557">Zuchner et al. (2006)</a> identified a heterozygous 827A-G transition in exon 9 of the MFN2 gene, resulting in a gln276-to-arg (Q276R) substitution. The patient's mother and sister both carried the mutation, but only had peripheral neuropathy without optic atrophy. <a href="#41" class="mim-tip-reference" title="Zuchner, S., De Jonghe, P., Jordanova, A., Claeys, K. G., Guergueltcheva, V., Cherninkova, S., Hamilton, S. R., Van Stavern, G., Krajewski, K. M., Stajich, J., Tournev, I., Verhoeven, K., Langerhorst, C. T., de Visser, M., Baas, F., Bird, T., Timmerman, V., Shy, M., Vance, J. M. <strong>Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2.</strong> Ann. Neurol. 59: 276-281, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16437557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16437557</a>] [<a href="https://doi.org/10.1002/ana.20797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16437557">Zuchner et al. (2006)</a> suggested incomplete penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16437557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 NEUROPATHY, HEREDITARY MOTOR AND SENSORY, TYPE VIA</strong>
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CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs119103265 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103265;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=rs119103265" 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=rs119103265" 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=RCV000002367 OR RCV000023711 OR RCV000195560 OR RCV000198024 OR RCV000857103 OR RCV000857104" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002367, RCV000023711, RCV000195560, RCV000198024, RCV000857103, RCV000857104" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002367...</a>
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<p>In a father and 2 sons with hereditary motor and sensory neuropathy type VIA (HMSN6A; <a href="/entry/601152">601152</a>), <a href="#41" class="mim-tip-reference" title="Zuchner, S., De Jonghe, P., Jordanova, A., Claeys, K. G., Guergueltcheva, V., Cherninkova, S., Hamilton, S. R., Van Stavern, G., Krajewski, K. M., Stajich, J., Tournev, I., Verhoeven, K., Langerhorst, C. T., de Visser, M., Baas, F., Bird, T., Timmerman, V., Shy, M., Vance, J. M. <strong>Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2.</strong> Ann. Neurol. 59: 276-281, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16437557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16437557</a>] [<a href="https://doi.org/10.1002/ana.20797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16437557">Zuchner et al. (2006)</a> identified a heterozygous 1090C-T transition in exon 11 of the MFN2 gene, resulting in an arg364-to-trp (R364W) substitution. All patients had a severe form of the disorder with neuropathy developing by age 1 year and optic atrophy by age 10 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16437557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Chung, K. W., Kim, S. B., Park, K. D., Choi, K. G., Lee, J. H., Eun, H. W., Suh, J. S., Hwang, J. H., Kim, W. K., Seo, B. C., Kim, S. H., Son, I. H., Kim, S. M., Sunwoo, I. N., Choi, B. O. <strong>Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations.</strong> Brain 129: 2103-2118, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16835246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16835246</a>] [<a href="https://doi.org/10.1093/brain/awl174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16835246">Chung et al. (2006)</a> reported 4 unrelated Korean families with early-onset neuropathy before 10 years of age and a heterozygous R364W mutation. In 1 family, only 1 of 3 mutation carriers had optic atrophy. In another family, both mutation carriers had optic atrophy. Optic atrophy was not present in the remaining 2 families, more consistent with a diagnosis of Charcot-Marie-Tooth disease-2A2A (CMT2A2A; <a href="/entry/609260">609260</a>). All except 1 patient had scoliosis and most had contractures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16835246" 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">rs119103266 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103266;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=rs119103266" 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=rs119103266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a father and son with hereditary motor and sensory neuropathy type VIA (HMSN6A; <a href="/entry/601152">601152</a>), <a href="#41" class="mim-tip-reference" title="Zuchner, S., De Jonghe, P., Jordanova, A., Claeys, K. G., Guergueltcheva, V., Cherninkova, S., Hamilton, S. R., Van Stavern, G., Krajewski, K. M., Stajich, J., Tournev, I., Verhoeven, K., Langerhorst, C. T., de Visser, M., Baas, F., Bird, T., Timmerman, V., Shy, M., Vance, J. M. <strong>Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2.</strong> Ann. Neurol. 59: 276-281, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16437557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16437557</a>] [<a href="https://doi.org/10.1002/ana.20797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16437557">Zuchner et al. (2006)</a> identified a heterozygous 617C-T transition in exon 7 of the MFN2 gene, resulting in a thr206-to-ile (T206I) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16437557" 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 LIPOMATOSIS, MULTIPLE SYMMETRIC, WITH OR WITHOUT AXONAL PERIPHERAL NEUROPATHY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs119103267 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103267;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/rs119103267?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=rs119103267" 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=rs119103267" 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=RCV000002369 OR RCV000199654 OR RCV000239892 OR RCV000472857 OR RCV000624830 OR RCV000778183 OR RCV001173687 OR RCV001775061 OR RCV002247240 OR RCV002285136 OR RCV002476912 OR RCV002508915 OR RCV003231070 OR RCV003319157" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002369, RCV000199654, RCV000239892, RCV000472857, RCV000624830, RCV000778183, RCV001173687, RCV001775061, RCV002247240, RCV002285136, RCV002476912, RCV002508915, RCV003231070, RCV003319157" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002369...</a>
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<p><strong><em>Multiple Symmetric Lipomatosis With or Without Axonal Peripheral Neuropathy</em></strong></p><p>
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In a 33-year-old woman (CMT40) with multiple symmetric lipomatosis (MSL; <a href="/entry/151800">151800</a>) and early-onset severe axonal peripheral neuropathy, <a href="#27" class="mim-tip-reference" title="Nicholson, G. A., Magdelaine, C., Zhu, D., Grew, S., Ryan, M. M., Sturtz, F., Vallat, J.-M., Ouvrier, R. A. <strong>Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations.</strong> Neurology 70: 1678-1681, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18458227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18458227</a>] [<a href="https://doi.org/10.1212/01.wnl.0000311275.89032.22" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18458227">Nicholson et al. (2008)</a> identified a homozygous c.2119C-T transition in the MFN2 gene, resulting in an arg707-to-trp (R707W) substitution at a highly conserved residue. Each parent was heterozygous for the mutation and showed mild features of a peripheral neuropathy, although they were not diagnosed with the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18458227" 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 (patients 1 and 2), born of consanguineous Irish parents, with MSL and mild axonal peripheral neuropathy, <a href="#36" class="mim-tip-reference" title="Sawyer, S. L., Cheuk-Him Ng, A., Innes, A. M., Wagner, J. D., Dyment, D. A., Tetreault, M., Care4Rare Canada Consortium, Majewski, J., Boycott, K. M., Screaton, R. A., Nicholson, G. <strong>Homozygous mutations in MFN2 cause multiple symmetric lipomatosis associated with neuropathy.</strong> Hum. Molec. Genet. 24: 5109-5114, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26085578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26085578</a>] [<a href="https://doi.org/10.1093/hmg/ddv229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26085578">Sawyer et al. (2015)</a> identified a homozygous c.2119C-T transition (c.2119C-T, NM_001127660) in exon 17 of the MFN2 gene. The mutation, which was found by whole-exome sequencing, was not present in their unaffected sibs. The mutation occurred within the heptad repeat 2 domain at the C terminal of MFN2, which is though to permit homotypic interactions and heterotypic binding to MFN1 (<a href="/entry/608506">608506</a>). It was found in the heterozygous state at a low frequency in the ExAC database (frequency of 0.0003). In vitro expression studies in MFN2-null cells showed that the R707W mutant had a reduced capacity to tubulate mitochondria. In addition, mitochondria in mutant cells were prone to aggregation, were defective in forming homooligomers, and formed smaller oligomeric complexes compared to wildtype MFN2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26085578" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Carr, A. S, Polke, J. M., Wilson, J., Pelayo-Negro, A. L., Laura, M., Nanji, T., Holt, J., Vaughan, J., Rankin, J., Sweeney, M. G., Blake, J., Houlden, H., Reilly, M. M. <strong>MFN2 deletion of exons 7 and 8: founder mutation in the UK population.</strong> J. Peripher. Nerv. Syst. 20: 67-71, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26114802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26114802</a>] [<a href="https://doi.org/10.1111/jns.12117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26114802">Carr et al. (2015)</a> reported a 44-year-old woman (patient 4) of UK ancestry with MSL and early-onset axonal neuropathy who was compound heterozygous for 2 mutations in the MFN2 gene: an exon 7-8 deletion (<a href="#0018">608507.0018</a>) and R707W. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26114802" 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 3 patients (P2, P3, and P4) from 2 unrelated European families with MSL, <a href="#33" class="mim-tip-reference" title="Rocha, N., Bulger, D. A., Frontini, A., Titheradge, H., Gribsholt, S. B., Knox, R., Page, M., Harris, J., Payne, F., Adams, C., Sleigh, A., Crawford, J., and 19 others. <strong>Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression.</strong> eLife 6: e23813, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28414270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28414270</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28414270[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.7554/eLife.23813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28414270">Rocha et al. (2017)</a> identified a homozygous R707W mutation in the MFN2 gene. Another patient with the disorder (P1) was compound heterozygous for R707W and arg343del (<a href="#0023">608507.0023</a>). The mutations, which were found by exome sequencing or direct Sanger sequencing, segregated with the disorder in the families from whom parental DNA was available for study. P1 and P4 showed evidence of a peripheral neuropathy, whereas sibs P2 and P3 did not. Studies of abnormal adipose tissue showed hyperplasia of UCP1 (<a href="/entry/113730">113730</a>)-negative unilocular adipocytes and proliferation of round, enlarged mitochondria with fragmented cristae. Transcriptome analysis of adipose tissue showed perturbation of gene expression related to mitochondrial dysfunction and oxidative phosphorylation. There was also alteration of genes related to cellular stress response pathways, including oxidative stress and unfolded protein response pathways, and upregulation of signatures related to tissue proliferation and survival. Examination of gene expression patterns identified the overgrown adipose tissue as white adipose tissue. In contrast, patient fibroblasts showed normal MFN2 expression and appropriate mitochondrial localization with normal mitochondria. These findings suggested that the abnormalities resulting from MFN2 mutations are tissue-specific. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28414270" 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 6 adult patients from 5 European families with MSL and axonal peripheral neuropathy, <a href="#6" class="mim-tip-reference" title="Capel, E., Vatier, C., Cervera, P., Stojkovic, T., Disse, E., Cottereau, A.-S., Auclair, M., Verpont, M.-C., Mosbah, H., Gourdy, P., Barraud, S., Miquel, A., and 12 others. <strong>MFN2-associated lipomatosis: clinical spectrum and impact on adipose tissue.</strong> J. Clin. Lipid. 12: 1420-1435, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30158064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30158064</a>] [<a href="https://doi.org/10.1016/j.jacl.2018.07.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30158064">Capel et al. (2018)</a> identified a homozygous R707W mutation in the MFN2 gene. Patient-derived lipomatous adipose tissue showed weak expression of the brown fat marker UCP1, and increased expression of thermogenic markers CITED1 (<a href="/entry/300149">300149</a>) and FGF21 (<a href="/entry/609436">609436</a>). Ultrastructural studies showed enlargement of the cytoplasmic ring of adipocytes and increased numbers of enlarged mitochondria with disorganized cristae or double membrane structures, suggestive of mitophagy. Gene expression studies of lipomatous tissue showed normal MFN2 expression and decreased expression of leptin and adiponectin. UCP1 expression was decreased, and CITED1 and FGF21 expression were increased. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30158064" 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>Charcot-Marie-Tooth Disease 2A2B</em></strong></p><p>
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In 3 sibs (patients 6-8) with autosomal recessive inheritance of severe early-onset Charcot-Marie-Tooth disease-2A2B (CMT2A2B; <a href="/entry/617087">617087</a>), <a href="#5" class="mim-tip-reference" title="Calvo, J., Funalot, B., Ouvrier, R. A., Lazaro, L., Toutain, A., De Mas, P., Bouche, P., Gilbert-Dussardier, B., Arne-Bes, M.-C., Carriere, J.-P., Journel, H., Minot-Myhie, M.-C., Guillou, C., Ghorab, K., Magy, L., Sturtz, F., Vallat, J.-M., Magdelaine, C. <strong>Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations.</strong> Arch. Neurol. 66: 1511-1516, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20008656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20008656</a>] [<a href="https://doi.org/10.1001/archneurol.2009.284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20008656">Calvo et al. (2009)</a> identified compound heterozygous missense mutations in the MFN2 gene: R707W and a c.322G-A transition in exon 5, resulting in a gly108-to-arg (G108R; <a href="#0022">608507.0022</a>) substitution in the GTPase domain. The patients, who were 19, 24, and 25 years of age, were not noted to have lipomatosis. Each of their unaffected parents was heterozygous for 1 of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20008656" 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">rs119103268 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103268;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=rs119103268" 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=rs119103268" 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 Italian father and 2 sons with peripheral neuropathy, <a href="#13" class="mim-tip-reference" title="Del Bo, R., Moggio, M., Rango, M., Bonato, S., D'Angelo, M. G., Ghezzi, S., Airoldi, G., Bassi, M. T., Guglieri, M., Napoli, L., Lamperti, C., Corti, S., Federico, A., Bresolin, N., Comi, G. P. <strong>Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction.</strong> Neurology 71: 1959-1966, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18946002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18946002</a>] [<a href="https://doi.org/10.1212/01.wnl.0000327095.32005.a4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18946002">Del Bo et al. (2008)</a> identified a heterozygous c.310C-T transition in exon 4 of the MFN2 gene, resulting in an arg104-to-trp (R104W) substitution at a highly conserved residue in the GTPase domain. The phenotype was highly variable within the family. The father had a symmetric axonal, predominantly motor polyneuropathy, spastic gait, and pes cavus, consistent with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; <a href="/entry/609260">609260</a>), as well as impaired nocturnal vision and sensorineural hearing loss, consistent with hereditary motor and sensory neuropathy type VIA (HMSN6A; <a href="/entry/601152">601152</a>). He also showed cognitive decline first noted in his forties. Both sons had delayed motor and language development, decreased IQ, steppage gait, distal muscle weakness and atrophy, and axonal sensorimotor neuropathy at ages 10 and 7 years, respectively. One son also had optic nerve dysfunction. MR spectroscopy (MRS) in the father suggested a defect in mitochondrial energy metabolism in the occipital cortex. <a href="#13" class="mim-tip-reference" title="Del Bo, R., Moggio, M., Rango, M., Bonato, S., D'Angelo, M. G., Ghezzi, S., Airoldi, G., Bassi, M. T., Guglieri, M., Napoli, L., Lamperti, C., Corti, S., Federico, A., Bresolin, N., Comi, G. P. <strong>Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction.</strong> Neurology 71: 1959-1966, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18946002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18946002</a>] [<a href="https://doi.org/10.1212/01.wnl.0000327095.32005.a4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18946002">Del Bo et al. (2008)</a> suggested that central nervous system involvement and cognitive impairment may be other phenotypic features of MFN2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18946002" 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, AXONAL, TYPE 2A2A</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs138382758 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs138382758;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/rs138382758?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=rs138382758" 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=rs138382758" 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=RCV000002372 OR RCV000196650 OR RCV000312138 OR RCV000487518 OR RCV001086652 OR RCV001172693 OR RCV001814957 OR RCV002390086 OR RCV004814803 OR RCV004814804" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002372, RCV000196650, RCV000312138, RCV000487518, RCV001086652, RCV001172693, RCV001814957, RCV002390086, RCV004814803, RCV004814804" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002372...</a>
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<p><a href="#8" class="mim-tip-reference" title="Casasnovas, C., Banchs, I., Cassereau, J., Gueguen, N., Chevrollier, A., Martinez-Matos, J. A., Bonneau, D., Volpini, V. <strong>Phenotypic spectrum of MFN2 mutations in the Spanish population.</strong> J. Med. Genet. 47: 249-256, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19889647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19889647</a>] [<a href="https://doi.org/10.1136/jmg.2009.072488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19889647">Casasnovas et al. (2010)</a> identified a heterozygous 1403G-A transition in exon 14 of the MFN2 gene, resulting in an arg468-to-his (R468H) substitution, in affected members of 6 (42.8%) of 14 unrelated Spanish families with autosomal dominant Charcot-Marie-Tooth disease-2A2A (CMT2A2A; <a href="/entry/609260">609260</a>). All patients with the R468H mutation had either mild or moderate disease that presented late in adult life in the third to fifth decade. Fibroblasts from 1 patient with the R468H mutation showed a mitochondrial coupling defect, a 50% decrease in ATP production, and an increase of the respiration rate linked to complex II. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19889647" 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, AXONAL, TYPE 2A2A</strong>
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MFN2, IVS13DS, T-C, +2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs111723244 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111723244;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=rs111723244" 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=rs111723244" 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=RCV000023713 OR RCV000789373" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023713, RCV000789373" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023713...</a>
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<p>In 3 sibs with a severe form of adult-onset Charcot-Marie-Tooth disease-2A2A (CMT2A2A; <a href="/entry/608260">608260</a>) who all developed a fatal subacute encephalopathy, <a href="#4" class="mim-tip-reference" title="Boaretto, F., Vettori, A., Casarin, A., Vazza, G., Muglia, M., Rossetto, M. G., Cavallaro, T., Rizzuto, N., Carelli, V., Salviati, L., Mostacciuolo, M. L., Martinuzzi, A. <strong>Severe CMT type 2 with fatal encephalopathy associated with a novel MFN2 splicing mutation.</strong> Neurology 74: 1919-1921, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20530328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20530328</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181e240f9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20530328">Boaretto et al. (2010)</a> identified a heterozygous T-to-C transition (1392+2T-C) in intron 13 of the MFN2 gene. Their father had died at age 61 of a similar disorder. The mutation was not found in 200 control chromosomes, but was present in an unaffected 64-year-old sister, indicating incomplete penetrance. RT-PCR analysis showed that the splice site mutation resulted in 4 aberrant MFN2 transcripts and completely abolished correct splicing of exon 13. There were different splicing patterns in the cell lines, suggesting that activation of cryptic splice sites may be under control of tissue-specific factors. <a href="#4" class="mim-tip-reference" title="Boaretto, F., Vettori, A., Casarin, A., Vazza, G., Muglia, M., Rossetto, M. G., Cavallaro, T., Rizzuto, N., Carelli, V., Salviati, L., Mostacciuolo, M. L., Martinuzzi, A. <strong>Severe CMT type 2 with fatal encephalopathy associated with a novel MFN2 splicing mutation.</strong> Neurology 74: 1919-1921, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20530328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20530328</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181e240f9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20530328">Boaretto et al. (2010)</a> noted the unusual encephalopathy present in this family, and suggested that the nature of the mutation may have put sensitive areas of the brain in a precarious energetic equilibrium. However, unknown genetic, epigenetic factors, or environmental factors likely played a role in the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20530328" 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 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2B, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906990 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906990;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/rs387906990?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=rs387906990" 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=rs387906990" 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=RCV000023714 OR RCV000235670 OR RCV000456775" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023714, RCV000235670, RCV000456775" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023714...</a>
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<p>In 2 British sibs with autosomal recessive inheritance of severe early-onset Charcot-Marie-Tooth disease-2A2B (CMT2A2B; <a href="/entry/617087">617087</a>), <a href="#31" class="mim-tip-reference" title="Polke, J. M., Laura, M., Pareyson, D., Taroni, F., Milani, M., Bergamin, G., Gibbons, V. S., Houlden, H., Chamley, S. C., Blake, J., DeVile, C., Sandford, R., Sweeney, M. G., Davis, M. B., Reilly, M. M. <strong>Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations.</strong> Neurology 77: 168-173, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21715711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21715711</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182242d4d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21715711">Polke et al. (2011)</a> identified compound heterozygosity for 2 mutations in the MFN2 gene: a 647T-C transition in exon 7, resulting in a phe216-to-ser (F216S) substitution on the maternal allele, and a deletion of exons 7 and 8 (<a href="#0018">608507.0018</a>) on the paternal allele. Transcript analysis showed low levels of a shortened transcript from the paternal allele, in which exon 6 was spliced to exon 9, suggested that some of the mutant transcript was subject to nonsense-mediated mRNA decay. If translated, the deletion transcript would result in a truncated out-of-frame protein lacking several important domains. Thus, it could represent either a null mutation or have a dominant-negative effect with reduced penetrance if coexpressed with a normal allele. The patients had onset at 12 and 18 months, respectively, of foot drop associated with marked upper and lower limb muscle weakness. Pinprick sensation was decreased, whereas vibration sense was basically preserved. One patient had optic atrophy and the other had pale optic disc; both were wheelchair-bound later in childhood. Each parent was clinically unaffected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21715711" 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>.0018 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2B, AUTOSOMAL RECESSIVE</strong>
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LIPOMATOSIS, MULTIPLE SYMMETRIC, WITH AXONAL PERIPHERAL NEUROPATHY, INCLUDED
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000023715 OR RCV003231109" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023715, RCV003231109" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023715...</a>
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<p>For discussion of the deletion of exons 7 and 8 in the MFN2 gene that was found in compound heterozygous state in 2 sibs of British descent with autosomal recessive inheritance of severe early-onset Charcot-Marie-Tooth disease-2A2B (CMT2A2B; <a href="/entry/609260">609260</a>) by <a href="#31" class="mim-tip-reference" title="Polke, J. M., Laura, M., Pareyson, D., Taroni, F., Milani, M., Bergamin, G., Gibbons, V. S., Houlden, H., Chamley, S. C., Blake, J., DeVile, C., Sandford, R., Sweeney, M. G., Davis, M. B., Reilly, M. M. <strong>Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations.</strong> Neurology 77: 168-173, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21715711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21715711</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182242d4d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21715711">Polke et al. (2011)</a>, see <a href="#0017">608507.0017</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21715711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Carr, A. S, Polke, J. M., Wilson, J., Pelayo-Negro, A. L., Laura, M., Nanji, T., Holt, J., Vaughan, J., Rankin, J., Sweeney, M. G., Blake, J., Houlden, H., Reilly, M. M. <strong>MFN2 deletion of exons 7 and 8: founder mutation in the UK population.</strong> J. Peripher. Nerv. Syst. 20: 67-71, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26114802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26114802</a>] [<a href="https://doi.org/10.1111/jns.12117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26114802">Carr et al. (2015)</a> reported 3 additional patients of UK ancestry with autosomal recessive early-onset axonal CMT2A2B due to compound heterozygous mutations in the MFN2 gene. All patients carried the exon 7-8 deletion on 1 allele, and haplotype analysis of these patients and the sibs reported by <a href="#31" class="mim-tip-reference" title="Polke, J. M., Laura, M., Pareyson, D., Taroni, F., Milani, M., Bergamin, G., Gibbons, V. S., Houlden, H., Chamley, S. C., Blake, J., DeVile, C., Sandford, R., Sweeney, M. G., Davis, M. B., Reilly, M. M. <strong>Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations.</strong> Neurology 77: 168-173, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21715711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21715711</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182242d4d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21715711">Polke et al. (2011)</a> indicated a founder effect in this population. Two of the patients (families 2 and 3) carried a T362M (<a href="#0019">608507.0019</a>) mutation on the other allele. The patient in family 4, who had multiple symmetric lipomatosis (MSL; <a href="/entry/151800">151800</a>) with axonal peripheral neuropathy, carried a R707W (<a href="#0013">608507.0013</a>) mutation on the other allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26114802+21715711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906991 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906991;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/rs387906991?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=rs387906991" 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=rs387906991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a Korean mother and daughter with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; <a href="/entry/609260">609260</a>), <a href="#11" class="mim-tip-reference" title="Chung, K. W., Kim, S. B., Park, K. D., Choi, K. G., Lee, J. H., Eun, H. W., Suh, J. S., Hwang, J. H., Kim, W. K., Seo, B. C., Kim, S. H., Son, I. H., Kim, S. M., Sunwoo, I. N., Choi, B. O. <strong>Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations.</strong> Brain 129: 2103-2118, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16835246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16835246</a>] [<a href="https://doi.org/10.1093/brain/awl174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16835246">Chung et al. (2006)</a> identified a heterozygous 1085C-T transition in the MFN2 gene, resulting in a thr362-to-met (T362M) substitution. The patients had late onset and a mild phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16835246" 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 adult Italian sibs with autosomal recessive inheritance of severe early-onset CMT2A2B (<a href="/entry/617087">617087</a>), <a href="#31" class="mim-tip-reference" title="Polke, J. M., Laura, M., Pareyson, D., Taroni, F., Milani, M., Bergamin, G., Gibbons, V. S., Houlden, H., Chamley, S. C., Blake, J., DeVile, C., Sandford, R., Sweeney, M. G., Davis, M. B., Reilly, M. M. <strong>Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations.</strong> Neurology 77: 168-173, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21715711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21715711</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182242d4d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21715711">Polke et al. (2011)</a> identified compound heterozygosity for 2 mutations in the MFN2 gene: a T362M substitution on the maternal allele, and a 3-bp in-frame deletion (113delAGA; <a href="#0020">608507.0020</a>) resulting in a deletion of lys38 (lys38del), presumably from the paternal allele, although no DNA was available from the deceased father. The patients had onset of foot drop and upper and lower limb weakness at age 3 years. They also had decreased pinprick and vibration senses, more severe in the lower limbs, kyphosis, pale optic discs, visual loss, severe facial weakness, and respiratory muscle weakness. One had hearing loss and vocal cord palsy. Both were wheelchair-bound. Nerve conduction studies showed absence of nerve conduction in 1 patient tested. Neither parent was affected. <a href="#31" class="mim-tip-reference" title="Polke, J. M., Laura, M., Pareyson, D., Taroni, F., Milani, M., Bergamin, G., Gibbons, V. S., Houlden, H., Chamley, S. C., Blake, J., DeVile, C., Sandford, R., Sweeney, M. G., Davis, M. B., Reilly, M. M. <strong>Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations.</strong> Neurology 77: 168-173, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21715711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21715711</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182242d4d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21715711">Polke et al. (2011)</a> noted that the T362M mutation had also been reported in families with dominant transmission, suggesting that it has a dominant-negative effect; the pathogenic effect of the lys38 deletion mutation was unknown, although it was not found in 550 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21715711" 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 32-year-old woman (CMT742) with autosomal recessive CMT2A2B, <a href="#27" class="mim-tip-reference" title="Nicholson, G. A., Magdelaine, C., Zhu, D., Grew, S., Ryan, M. M., Sturtz, F., Vallat, J.-M., Ouvrier, R. A. <strong>Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations.</strong> Neurology 70: 1678-1681, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18458227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18458227</a>] [<a href="https://doi.org/10.1212/01.wnl.0000311275.89032.22" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18458227">Nicholson et al. (2008)</a> identified compound heterozygosity for 2 missense mutations in the MFN2 gene: T362M and A164V (<a href="#0021">608507.0021</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18458227" 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">rs1478175861 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1478175861;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=rs1478175861" 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=rs1478175861" 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=RCV000023712 OR RCV000790039 OR RCV001288126 OR RCV005089307" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023712, RCV000790039, RCV001288126, RCV005089307" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023712...</a>
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<p>For discussion of the 3-bp deletion in the MFN2 gene (113delAGA) that was found in compound heterozygous state in patients with autosomal recessive inheritance of severe early-onset Charcot-Marie-Tooth disease-2A2B (CMT2A2B; <a href="/entry/617087">617087</a>) by <a href="#31" class="mim-tip-reference" title="Polke, J. M., Laura, M., Pareyson, D., Taroni, F., Milani, M., Bergamin, G., Gibbons, V. S., Houlden, H., Chamley, S. C., Blake, J., DeVile, C., Sandford, R., Sweeney, M. G., Davis, M. B., Reilly, M. M. <strong>Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations.</strong> Neurology 77: 168-173, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21715711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21715711</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182242d4d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21715711">Polke et al. (2011)</a>, see <a href="#0019">608507.0019</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21715711" 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 a 32-year-old woman (CMT742) with autosomal recessive early-onset Charcot-Marie-Tooth disease-2A2B (CMT2A2B; <a href="/entry/617087">617087</a>), <a href="#27" class="mim-tip-reference" title="Nicholson, G. A., Magdelaine, C., Zhu, D., Grew, S., Ryan, M. M., Sturtz, F., Vallat, J.-M., Ouvrier, R. A. <strong>Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations.</strong> Neurology 70: 1678-1681, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18458227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18458227</a>] [<a href="https://doi.org/10.1212/01.wnl.0000311275.89032.22" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18458227">Nicholson et al. (2008)</a> identified compound heterozygous missense mutations in the MFN2 gene: a c.491C-T transition, resulting in an ala164-to-val (A164V) substitution, and a c.1085C-T transition, resulting in a thr362-to-met (T362M; <a href="#0019">608507.0019</a>) substitution. The patient had onset of symptoms at 3 years of age. She had delayed motor development and was wheelchair-bound at age 10. Other features included mild deafness, scoliosis, and high-pitched voice. Her parents, who were each heterozygous for one of the mutations, showed mild features of the disorder, including pes cavus and inability to heel-walk. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18458227" 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">rs1569829573 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569829573;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=rs1569829573" 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=rs1569829573" 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=RCV000790317 OR RCV003234565" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000790317, RCV003234565" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000790317...</a>
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<p>For discussion of the c.322G-A transition in exon 5 of the MFN2 gene, resulting in a gly108-to-arg (G108R) substitution, that was found in compound heterozygous state in 3 sibs with autosomal recessive inheritance of severe early-onset Charcot-Marie-Tooth disease-2A2B (CMT2A2B; <a href="/entry/617087">617087</a>) by <a href="#5" class="mim-tip-reference" title="Calvo, J., Funalot, B., Ouvrier, R. A., Lazaro, L., Toutain, A., De Mas, P., Bouche, P., Gilbert-Dussardier, B., Arne-Bes, M.-C., Carriere, J.-P., Journel, H., Minot-Myhie, M.-C., Guillou, C., Ghorab, K., Magy, L., Sturtz, F., Vallat, J.-M., Magdelaine, C. <strong>Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations.</strong> Arch. Neurol. 66: 1511-1516, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20008656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20008656</a>] [<a href="https://doi.org/10.1001/archneurol.2009.284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20008656">Calvo et al. (2009)</a>, see <a href="#0013">608507.0013</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20008656" 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>.0023 LIPOMATOSIS, MULTIPLE SYMMETRIC, WITH AXONAL PERIPHERAL NEUROPATHY</strong>
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MFN2, 3-BP DEL, ARG343DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003232881" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003232881" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003232881</a>
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<p>For discussion of the in-frame 3-bp deletion in the MFN2 gene, resulting in the deletion of residue arg343 (arg343del), that was found in compound heterozygous state in a patient with multiple symmetric lipomatosis with axonal peripheral neuropathy (MSL; <a href="/entry/151800">151800</a>) by <a href="#33" class="mim-tip-reference" title="Rocha, N., Bulger, D. A., Frontini, A., Titheradge, H., Gribsholt, S. B., Knox, R., Page, M., Harris, J., Payne, F., Adams, C., Sleigh, A., Crawford, J., and 19 others. <strong>Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression.</strong> eLife 6: e23813, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28414270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28414270</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28414270[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.7554/eLife.23813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28414270">Rocha et al. (2017)</a>, see <a href="#0013">608507.0013</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28414270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>REFERENCES</strong>
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<a id="Bach2003" class="mim-anchor"></a>
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Bach, D., Pich, S., Soriano, F. X., Vega, N., Baumgartner, B., Oriola, J., Daugaard, J. R., Lloberas, J., Camps, M., Zierath, J. R., Rabasa-Lhoret, R., Wallberg-Henriksson, H., Laville, M., Palacin, M., Vidal, H., Rivera, F., Brand, M., Zorzano, A.
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<strong>Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism: a novel regulatory mechanism altered in obesity.</strong>
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J. Biol. Chem. 278: 17190-17197, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12598526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12598526</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12598526" 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/10.1074/jbc.M212754200" target="_blank">Full Text</a>]
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<a id="Ben Othmane1993" class="mim-anchor"></a>
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Ben Othmane, K., Middleton, L. T., Loprest, L. J., Wilkinson, K. M., Lennon, F., Rozear, M. P., Stajich, J. M., Gaskell, P. C., Roses, A. D., Pericak-Vance, M. A., Vance, J. M.
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<strong>Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity.</strong>
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Genomics 17: 370-375, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8406488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8406488</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8406488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1993.1334" target="_blank">Full Text</a>]
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<a id="Bissar-Tadmouri2004" class="mim-anchor"></a>
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Bissar-Tadmouri, N., Nelis, E., Zuchner, S., Parman, Y., Deymeer, F., Serdaroglu, P., De Jonghe, P., Van Gerwen, V., Timmerman, V., Schroder, J. M., Battaloglu, E.
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<strong>Absence of KIF1B mutation in a large Turkish CMT2A family suggests involvement of a second gene.</strong>
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Neurology 62: 1522-1525, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15136675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15136675</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15136675" 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/10.1212/01.wnl.0000123253.57555.3a" target="_blank">Full Text</a>]
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<a id="Boaretto2010" class="mim-anchor"></a>
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Boaretto, F., Vettori, A., Casarin, A., Vazza, G., Muglia, M., Rossetto, M. G., Cavallaro, T., Rizzuto, N., Carelli, V., Salviati, L., Mostacciuolo, M. L., Martinuzzi, A.
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<strong>Severe CMT type 2 with fatal encephalopathy associated with a novel MFN2 splicing mutation.</strong>
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Neurology 74: 1919-1921, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20530328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20530328</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20530328" 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.0b013e3181e240f9" target="_blank">Full Text</a>]
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<a id="Calvo2009" class="mim-anchor"></a>
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Calvo, J., Funalot, B., Ouvrier, R. A., Lazaro, L., Toutain, A., De Mas, P., Bouche, P., Gilbert-Dussardier, B., Arne-Bes, M.-C., Carriere, J.-P., Journel, H., Minot-Myhie, M.-C., Guillou, C., Ghorab, K., Magy, L., Sturtz, F., Vallat, J.-M., Magdelaine, C.
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<strong>Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations.</strong>
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Arch. Neurol. 66: 1511-1516, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20008656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20008656</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20008656" 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/10.1001/archneurol.2009.284" target="_blank">Full Text</a>]
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<a id="Capel2018" class="mim-anchor"></a>
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Capel, E., Vatier, C., Cervera, P., Stojkovic, T., Disse, E., Cottereau, A.-S., Auclair, M., Verpont, M.-C., Mosbah, H., Gourdy, P., Barraud, S., Miquel, A., and 12 others.
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<strong>MFN2-associated lipomatosis: clinical spectrum and impact on adipose tissue.</strong>
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J. Clin. Lipid. 12: 1420-1435, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30158064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30158064</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30158064" 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.jacl.2018.07.009" target="_blank">Full Text</a>]
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<a id="Carr2015" class="mim-anchor"></a>
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Carr, A. S, Polke, J. M., Wilson, J., Pelayo-Negro, A. L., Laura, M., Nanji, T., Holt, J., Vaughan, J., Rankin, J., Sweeney, M. G., Blake, J., Houlden, H., Reilly, M. M.
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<strong>MFN2 deletion of exons 7 and 8: founder mutation in the UK population.</strong>
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J. Peripher. Nerv. Syst. 20: 67-71, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26114802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26114802</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26114802" 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.12117" target="_blank">Full Text</a>]
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<a id="Casasnovas2010" class="mim-anchor"></a>
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Casasnovas, C., Banchs, I., Cassereau, J., Gueguen, N., Chevrollier, A., Martinez-Matos, J. A., Bonneau, D., Volpini, V.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19889647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19889647</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19889647" 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.2009.072488" target="_blank">Full Text</a>]
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<a id="Chen2003" class="mim-anchor"></a>
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Chen, H., Detmer, S. A., Ewald, A. J., Griffin, E. E., Fraser, S. E., Chan, D. C.
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<strong>Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12527753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12527753</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12527753[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=12527753" 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/10.1083/jcb.200211046" target="_blank">Full Text</a>]
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<a id="Chen2013" class="mim-anchor"></a>
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Chen, Y., Dorn, G. W., II.
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<strong>PINK1-phosphorylated mitofusin 2 is a parkin receptor for culling damaged mitochondria.</strong>
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Science 340: 471-475, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23620051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23620051</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23620051[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=23620051" 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.1231031" target="_blank">Full Text</a>]
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<a id="Chung2006" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1093/brain/awl174" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature07534" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000311275.89032.22" target="_blank">Full Text</a>]
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Zuchner, S., Mersiyanova, I. V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali, E. L., Zappia, M., Nelis, E., Patitucci, A., Senderek, J., Parman, Y., Evgrafov, O., and 10 others.
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<strong>Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.</strong>
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Nature Genet. 36: 449-451, 2004. Note: Erratum: Nature Genet. 36: 660 only, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15064763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15064763</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15064763" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1341" target="_blank">Full Text</a>]
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</p>
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<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 05/26/2023
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 03/29/2021<br>Hilary J. Vernon - updated : 10/20/2020<br>Bao Lige - updated : 08/28/2020<br>Ada Hamosh - updated : 10/09/2019<br>Ada Hamosh - updated : 09/27/2019<br>Ada Hamosh - updated : 05/29/2018<br>Ada Hamosh - updated : 12/14/2016<br>Cassandra L. Kniffin - updated : 08/24/2016<br>Cassandra L. Kniffin - updated : 6/14/2016<br>Ada Hamosh - updated : 1/31/2014<br>Ada Hamosh - updated : 5/29/2013<br>Cassandra L. Kniffin - updated : 3/11/2013<br>Cassandra L. Kniffin - updated : 11/2/2011<br>Cassandra L. Kniffin - updated : 6/20/2011<br>Cassandra L. Kniffin - updated : 3/22/2011<br>Cassandra L. Kniffin - updated : 5/27/2010<br>Cassandra L. Kniffin - updated : 3/1/2010<br>Cassandra L. Kniffin - updated : 1/11/2010<br>Cassandra L. Kniffin - updated : 3/16/2009<br>Ada Hamosh - updated : 1/6/2009<br>Patricia A. Hartz - updated : 10/29/2008<br>Cassandra L. Kniffin - updated : 9/25/2008<br>George E. Tiller - updated : 6/5/2008<br>Ada Hamosh - updated : 10/24/2006<br>Cassandra L. Kniffin - updated : 4/11/2006<br>Cassandra L. Kniffin - updated : 11/10/2005<br>Victor A. McKusick - updated : 2/21/2005<br>Cassandra L. Kniffin - updated : 1/31/2005<br>Cassandra L. Kniffin - updated : 4/5/2004
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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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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz : 3/3/2004
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 06/01/2023
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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">
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ckniffin : 05/26/2023<br>carol : 10/06/2022<br>carol : 03/29/2021<br>carol : 10/26/2020<br>carol : 10/20/2020<br>mgross : 08/28/2020<br>alopez : 10/09/2019<br>alopez : 09/27/2019<br>alopez : 05/29/2018<br>alopez : 05/29/2018<br>alopez : 12/14/2016<br>carol : 09/16/2016<br>ckniffin : 09/12/2016<br>carol : 08/29/2016<br>carol : 08/29/2016<br>ckniffin : 08/24/2016<br>carol : 06/14/2016<br>ckniffin : 6/14/2016<br>carol : 8/7/2015<br>mcolton : 8/5/2015<br>ckniffin : 8/4/2015<br>alopez : 6/17/2015<br>mcolton : 6/12/2015<br>alopez : 10/10/2014<br>alopez : 1/31/2014<br>alopez : 6/27/2013<br>alopez : 5/29/2013<br>alopez : 3/12/2013<br>ckniffin : 3/11/2013<br>terry : 8/3/2012<br>alopez : 1/9/2012<br>carol : 11/15/2011<br>ckniffin : 11/2/2011<br>wwang : 6/28/2011<br>ckniffin : 6/20/2011<br>wwang : 4/7/2011<br>ckniffin : 3/22/2011<br>wwang : 6/2/2010<br>ckniffin : 5/27/2010<br>wwang : 3/4/2010<br>ckniffin : 3/1/2010<br>wwang : 1/22/2010<br>ckniffin : 1/11/2010<br>wwang : 3/26/2009<br>ckniffin : 3/16/2009<br>alopez : 1/6/2009<br>terry : 1/6/2009<br>mgross : 10/29/2008<br>terry : 10/29/2008<br>wwang : 10/3/2008<br>ckniffin : 9/25/2008<br>wwang : 6/10/2008<br>terry : 6/5/2008<br>alopez : 11/6/2006<br>terry : 10/24/2006<br>carol : 4/14/2006<br>ckniffin : 4/11/2006<br>wwang : 11/17/2005<br>ckniffin : 11/10/2005<br>mgross : 3/15/2005<br>ckniffin : 3/4/2005<br>terry : 2/21/2005<br>ckniffin : 1/31/2005<br>alopez : 12/30/2004<br>alopez : 12/30/2004<br>terry : 12/29/2004<br>alopez : 6/10/2004<br>alopez : 5/3/2004<br>tkritzer : 4/5/2004<br>ckniffin : 4/5/2004<br>cwells : 3/3/2004
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<span class="mim-font">
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<strong>*</strong> 608507
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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MITOFUSIN 2; MFN2
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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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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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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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KIAA0214
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</span>
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</h4>
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</div>
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<div>
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MFN2</em></strong>
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</span>
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</p>
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</div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 128203003, 238902007;
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</span>
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<strong>
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<em>
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Cytogenetic location: 1p36.22
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:11,980,444-12,013,508 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</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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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="4">
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<span class="mim-font">
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1p36.22
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</span>
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</td>
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<td>
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<span class="mim-font">
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Charcot-Marie-Tooth disease, axonal, type 2A2A
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</span>
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</td>
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<td>
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<span class="mim-font">
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609260
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Charcot-Marie-Tooth disease, axonal, type 2A2B
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</span>
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</td>
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<td>
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<span class="mim-font">
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617087
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Hereditary motor and sensory neuropathy VIA
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</span>
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</td>
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<td>
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<span class="mim-font">
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601152
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Lipomatosis, multiple symmetric, with or without peripheral neuropathy
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</span>
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</td>
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<td>
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<span class="mim-font">
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151800
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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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>TEXT</strong>
|
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The size and arrangement of mitochondria differs with cell type, physiologic condition, and pathologic state. Mitofusins, such as MFN2, mediate the fusion of mitochondria and thereby contribute to the dynamic balance between fusion and fission that determines mitochondria morphology (Santel and Fuller, 2001). </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>Cloning and Expression</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 sequencing clones obtained from a size-fractionated immature myeloid cell line cDNA library, Nagase et al. (1996) cloned MFN2, which they designated KIAA0214. The deduced 757-amino acid protein contains an ATP/GTP-binding site motif. Northern blot analysis detected expression of MFN2 in all tissues and cell lines examined, with highest expression in heart and skeletal muscle. </p><p>By searching EST databases, Santel and Fuller (2001) found that KIAA0214 showed significant similarity to the Drosophila mitochondria fusion gene, Fzo, and they further characterized the cDNA clone. The deduced 757-amino acid protein contains an N-terminal GTPase domain and a transmembrane domain near the C terminus. MFN2 shares 60% identity with MFN1 (608506), with the most extensive homology in the GTPase domains. The N- and C-terminal ends are more variable. When stably expressed in COS-7 cells, MFN2 colocalized with mitochondrial markers. An internal region, including the predicted bipartite transmembrane domain, was sufficient to target MFN2 to mitochondria. </p><p>Bach et al. (2003) cloned rat Mfn2, which shares 95% identity to human MFN2. Northern blot analysis of human tissues detected a 4.7-kb transcript expressed at high levels in skeletal muscle and heart, and at lower levels in brain, kidney, and liver. Little to no expression was detected in other tissues. Very little Mfn2 was expressed in a rat myoblast cell line, but expression was induced following differentiation into myotubes. Western blot analysis detected rat Mfn2 at an apparent molecular mass of 110 kD in heart, skeletal muscle, brown adipose tissue, and kidney. Endogenous Mfn2 was enriched in mitochondrial fractions of these tissues. </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>Gene Structure</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>Casasnovas et al. (2010) noted that the MFN2 gene contains 19 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Mapping</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By radiation hybrid analysis and by examining a human-rodent hybrid panel, Nagase et al. (1996) mapped the MFN2 gene to chromosome 1. </p><p>Zuchner et al. (2004) stated that the MFN2 gene maps to chromosome 1p36.2, about 1.65 Mb centromeric to the KIF1B gene (605995), which is mutant in Charcot-Marie-Tooth disease-2A1 (CMT2A1; 118210). </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>Gene Function</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Santel and Fuller (2001) found that overexpression of MFN2 caused perinuclear mitochondrial clustering. Mutation analysis revealed that the C-terminal coiled-coil domain mediated mitochondrial clustering, and the GTPase domain mediated mitochondrial fusion. Furthermore, a GTPase-dead DRP1 (603850) caused similar mitochondrial clustering in transfected COS-7 cells, and COS-7 cells cotransfected with the GTPase-dead DRP1 and MFN2 developed mitochondrial filaments and networks that extended from the perinuclear mitochondrial cluster toward the cell periphery. Santel and Fuller (2001) concluded that the size and morphologic arrangement of mitochondria are due to a dynamic balance between MFN-dependent mitochondrial fusion and DRP1-dependent mitochondrial fission. </p><p>Bach et al. (2003) found that the induction of Mfn2 during differentiation in a rat myogenic cell line into myotubes paralleled the development of an extensive mitochondrial network. Overexpression of Mfn2 collapsed the network and mitochondria clustered around the nucleus. Knock-down of Mfn2 expression in muscle cells with mouse Mfn2 antisense sequence led to fragmentation of the mitochondrial network into independent clusters and loss of mitochondrial membrane potential. Reduced Mfn2 expression in rat myotubes and mouse fibroblasts was associated with a 30% reduction of glucose oxidation. Repression of Mfn2 expression also reduced mitochondrial membrane potential and cell respiration, and reduced mitochondrial proton leak. Bach et al. (2003) further found that Mfn2 expression was repressed in obesity, being reduced by 34% in muscle from obese rats, and reduced by 36% in muscle of obese human subjects. Expression in mitochondrial fractions was 39% lower in obese rats, and 43% lower in obese humans in comparison with lean controls. Bach et al. (2003) concluded that MFN2 expression is crucial in mitochondrial metabolism through the maintenance of the mitochondrial network architecture, and reduced MFN2 expression may explain some of the metabolic alterations associated with obesity. </p><p>Pich et al. (2005) showed that Mfn2 loss of function inhibited pyruvate, glucose, and fatty acid oxidation and reduced mitochondrial membrane potential, whereas Mfn2 gain of function increased glucose oxidation and mitochondrial membrane potential. Mfn2 loss of function repressed nuclear-encoded subunits of OXPHOS complexes I, II, III and V, whereas Mfn2 overexpression induced the subunits of complexes I, IV, and V. Obesity-induced Mfn2 deficiency in rat skeletal muscle was also associated with a decrease in the subunits of complexes I, II, III, and V. In addition, the effect of Mfn2 overexpression on mitochondrial metabolism was mimicked by a truncated Mfn2 mutant that was inactive as a mitochondrial fusion protein. Pich et al. (2005) concluded that Mfn2 triggers mitochondrial energization, at least in part, by regulating OXPHOS expression through signals that are independent of its role as a mitochondrial fusion protein. </p><p>Two members of the BCL2 family, BAX (600040) and BAK (600516), change intracellular location early in the promotion of apoptosis to concentrate in focal clusters at sites of mitochondrial division. Karbowski et al. (2006) reported that in healthy cells, BAX or BAK is required for normal fusion of mitochondria into elongated tubules. BAX seems to induce mitochondrial fusion by activating assembly of the large GTPase MFN2 and changing its submitochondrial distribution and membrane mobility--properties that correlate with different GTP-bound states of MFN2. Karbowski et al. (2006) concluded that BAX and BAK regulate mitochondrial dynamics in healthy cells and that BCL2 family members may also regulate apoptosis through organelle morphogenesis machineries. </p><p>Guo et al. (2007) found that a variety of apoptotic stimuli induced expression of Mfn2 in rat vascular smooth muscle cells (VSMCs). Overexpression of Mfn2 triggered apoptosis of VSMCs in culture and in balloon-injured rat carotid arteries, which helped prevent neointima formation after angioplasty. Conversely, Mfn2 silencing protected VSMCs against H2O2- or Mfn2 overexpression-induced apoptosis. The proapoptotic effect of Mfn2 was independent of its role in mitochondrial fusion and was mediated by inhibition of Akt (see AKT1; 164730) signaling, resulting in activation of the mitochondrial apoptotic pathway. Mfn2-induced apoptosis was blocked by overexpression of an active phosphoinositide 3-kinase (see PIK3CG; 601232) mutant or inhibition of Bclxl (600039) or caspase-9 (CASP9; 602234). Guo et al. (2007) concluded that, in addition to its antiproliferative effects, MFN2 is a primary determinant of VSMC apoptosis. </p><p>De Brito and Scorrano (2008) showed that MFN2 is enriched at the endoplasmic reticulum (ER)-mitochondria interface. Ablation or silencing of Mfn2 in mouse embryonic fibroblasts and HeLa cells disrupted ER morphology and loosened ER-mitochondria interactions, thereby reducing the efficiency of mitochondrial calcium uptake in response to stimuli that generate inositol-1,4,5-trisphosphate. An in vitro assay as well as genetic and biochemical evidences supported a model in which Mfn2 on the ER bridges the 2 organelles by engaging in homotypic and heterotypic complexes with Mfn1 (608506) or Mfn2 on the surface of mitochondria. Thus, de Brito and Scorrano (2008) concluded that Mfn2 tethers ER to mitochondria, a juxtaposition required for efficient mitochondrial calcium uptake. </p><p>Chen and Dorn (2013) demonstrated that the mitochondrial outer membrane guanosine triphosphatase MFN2 mediates parkin (602544) recruitment to damaged mitochondria. Parkin bound to MFN2 in a PINK1 (608309)-dependent manner; PINK1 phosphorylated MFN2 and promoted its parkin-mediated ubiquitination. Ablation of Mfn2 in mouse cardiac myocytes prevented depolarization-induced translocation of parkin to the mitochondria and suppressed mitophagy. Accumulation of morphologically and functionally abnormal mitochondria induced respiratory dysfunction in Mfn2-deficient mouse embryonic fibroblasts and cardiomyocytes and in parkin-deficient Drosophila heart tubes, causing dilated cardiomyopathy. Thus, Chen and Dorn (2013) concluded that MFN2 functions as a mitochondrial receptor for parkin and is required for quality control of cardiac mitochondria. </p><p>Kasahara et al. (2013) found that mitochondrial fusion was required for proper cardiomyocyte development. Ablation of mitochondrial fusion proteins Mfn1 and Mfn2 in the embryonic mouse heart, or gene trapping of Mfn2 or optic atrophy-1 (Opa1; 605290) in mouse embryonic stem cells, arrested mouse heart development and impaired differentiation of embryonic stem cells into cardiomyocytes. Gene expression profiling revealed decreased levels of transcription factors Tgf-beta (190180)/Bmp (see 112264), serum response factor (SRF; 600589), Gata4 (600576), and myocyte enhancer factor-2, linked to increased calcium-dependent calcineurin (see 114105) activity and Notch1 (190198) signaling that impaired embryonic stem cell differentiation. Kasahara et al. (2013) concluded that orchestration of cardiomyocyte differentiation by mitochondrial morphology revealed how mitochondria, calcium, and calcineurin interact to regulate Notch1 signaling. </p><p>Using RT-PCR analysis, Vadnais et al. (2014) showed that Mns1 (610766) and Mfn2 were highly expressed in mouse spermatogenic cells, with decreasing expression from pachytene spermatocytes to condensing spermatids. In spermatogenic cells, Mfn2 was expressed in mitochondria, and Mns1 in cytoplasm. Both proteins were also found in caput and cauda epididymal sperm and in male and female reproductive tissues. Immunoprecipitation and immunofluorescence analyses revealed that both proteins formed a complex in spermatogenic cells and colocalized to sperm flagellum. The results demonstrated that Mns1 and Mfn2 are an integral part of sperm flagellum and suggested that they play a role in flagellar biogenesis and/or function. </p><p>Luchsinger et al. (2016) showed in mice that the short isoform of a critical regulator of hematopoietic stem cells (HSCs), Prdm16 (605557), induces Mfn2, a protein involved in mitochondrial fusion and in tethering of mitochondria to the endoplasmic reticulum. Overexpression and deletion studies, including single-cell transplantation assays, revealed that Mfn2 is specifically required for the maintenance of HSCs with extensive lymphoid potential, but not, or less so, for the maintenance of myeloid-dominant HSCs. Mfn2 increased buffering of intracellular Ca(2+), an effect mediated through its endoplasmic reticulum-mitochondria tethering activity, thereby negatively regulating nuclear translocation and transcriptional activity of nuclear factor of activated T cells (Nfat; see 600489). Nfat inhibition rescued the effects of Mfn2 deletion in HSCs, demonstrating that negative regulation of Nfat is the prime downstream mechanism of Mfn2 in the maintenance of HSCs with extensive lymphoid potential. Mitochondria therefore have an important role in HSCs. Luchsinger et al. (2016) concluded that these findings provided a mechanism underlying clonal heterogeneity among HSCs and could lead to the design of approaches to bias HSC differentiation into desired lineages after transplantation. </p><p>Rocha et al. (2018) showed that MFN2 activity can be determined by met376 and his380 interactions with asp725 and leu727 and controlled by PINK1 kinase-mediated phosphorylation of adjacent MFN2 ser378. Small-molecule mimics of the peptide-peptide interface of MFN2 disrupted this interaction, allosterically activating MFN2 and promoting mitochondrial fusion. These first-in-class mitofusin agonists overcame dominant mitochondrial defects provoked in cultured neurons by CMT2A mutants MFN2 arg94 to gln (608507.0001) and MFN2 thr105 to met (T105M), as demonstrated by amelioration of mitochondrial dysmotility, fragmentation, depolarization, and clumping. A mitofusin agonist normalized axonal mitochondrial trafficking within sciatic nerves of MFN2 T105M mice, suggesting a therapeutic approach for CMT2A and other diseases of impaired neuronal mitochondrial dynamism and/or trafficking. </p><p>Franco et al. (2016) showed that mitofusins adopt either a fusion-constrained or a fusion-permissive molecular conformation, directed by specific intramolecular binding interactions, and demonstrated that mitofusin-dependent mitochondrial fusion can be regulated in mouse cells by targeting these conformational transitions. On the basis of this model, Franco et al. (2016) engineered a cell-permeant minipeptide to destabilize the fusion-constrained conformation of mitofusin and promote the fusion-permissive conformation, reversing mitochondrial abnormalities in cultured fibroblasts and neurons that harbor CMT2A-associated genetic defects. Franco et al. (2016) concluded that the relationship between the conformational plasticity of mitofusin-2 and mitochondrial dynamism revealed a central mechanism that regulates mitochondrial fusion, the manipulation of which can correct mitochondrial pathology triggered by defective or imbalanced mitochondrial dynamics. </p><p>Gong et al. (2015) found that Pink1 (608309)-Mfn2-parkin (602544)-mediated mitophagy directs the change in mitochondrial substrate preference in developing mouse hearts from carbohydrates to fatty acids. A Mfn2 mutant lacking Pink1 phosphorylation sites necessary for parkin binding (Mfn2 AA) inhibited mitochondrial parkin translocation, suppressing mitophagy without impairing mitochondrial fusion. Cardiac Parkin deletion or expression of Mfn2 AA from birth, but not after weaning, prevented postnatal mitochondrial maturation essential to survival. Five-week-old Mfn2 AA hearts retained a fetal mitochondrial transcriptional signature without normal increases in fatty acid metabolism and mitochondrial biogenesis genes. Myocardial fatty acylcarnitine levels and cardiomyocyte respiration induced by palmitoylcarnitine were concordantly depressed. Thus, instead of transcriptional reprogramming, fetal cardiomyocyte mitochondria undergo perinatal parkin-mediated mitophagy and replacement by mature adult mitochondria. Gong et al. (2015) concluded that mitophagic mitochondrial removal underlies developmental cardiomyocyte mitochondrial plasticity and metabolic transitioning of perinatal hearts. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p><strong><em>Peripheral Neuropathy</em></strong></p><p>
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In affected members of several families with autosomal dominant Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260), Zuchner et al. (2004) identified heterozygous mutations in the MFN2 gene (608507.0001-608507.0006). </p><p>Kijima et al. (2005) studied the MFN2 gene in 81 Japanese patients with axonal or unclassified CMT and detected 7 mutations in 7 unrelated patients. Six mutations were novel, and 1 was a de novo mutation. Most mutations were located within or immediately upstream of the GTPase domain or within 2 coiled-coil domains critical for mitochondrial targeting of MFN2. Kijima et al. (2005) stated that formation of the mitochondrial network would be required to maintain the functional peripheral nerve axon. </p><p>In affected members of 6 unrelated families with hereditary motor and sensory neuropathy with optic atrophy (HMSN6A; 601152), Zuchner et al. (2006) identified 6 different heterozygous mutations in the MFN2 gene (see, e.g., 608507.0009-608607.0012). </p><p>Chung et al. (2006) identified 10 pathogenic MFN2 mutations (see, e.g., 608507.0004; 608507.0009; 608507.0011) in 26 patients from 15 (24.2%) of 62 Korean families with CMT2A2 or HMSN VI. There were 2 main groups of patients, including those with early onset before 10 years and those with late onset after age 10 years. Those with early onset had a severe disorder, often with scoliosis and contractures, whereas those with later onset had a milder disorder and a higher frequency of unusual findings such as tremor, pain, and hearing loss. The severity of the disorder tended to be the same within families, suggesting a genotype/phenotype correlation. </p><p>In fibroblasts derived from CMT2A2 patients with MFN2 mutations (see, e.g., R94Q, 608507.0001), Guillet et al. (2010) found an uncoupling of mitochondrial oxygen consumption and decreased efficiency of oxygen utilization, but normal ATP production. Normal ATP production was maintained by an increased respiration rate, mainly involving complex II proteins. Mutant fibroblasts also showed overexpression and increased activity of ANT3 (SLC25A6; 300151), which was believed to result in reduced efficiency of oxidative phosphorylation. The findings suggested that MFN2 plays a role in controlling ATP/ADP exchange in mitochondria. </p><p>Calvo et al. (2009) identified 20 different missense mutations, including 10 novel mutations, in the MFN2 gene in 20 of 150 probands with CMT and a nerve conduction velocity (NCV) of 25 m/s or greater. Eighteen of the patients had been previously reported. The mutation frequency in CMT2 was 17.8% (19 of 107 patients) and in CMT1 was 2.3% (1 of 43). Four patients had proven de novo mutations, 8 families had autosomal dominant inheritance, and 3 had autosomal recessive inheritance; the remaining 5 patients were sporadic cases with heterozygous mutations. The phenotypes varied from mild forms to early-onset severe forms, and additional features, such as pyramidal signs or vasomotor dysfunction, were encountered in 8 patients (32%). The study indicated that MFN2 mutations are a frequent cause of CMT2, with variable severity and either dominant or recessive inheritance. Calvo et al. (2009) suggested that testing for mutations in MFN2 showed be a first-line analysis in axonal CMT regardless of the mode of inheritance or the severity of the peripheral neuropathy. </p><p>Casasnovas et al. (2010) identified 9 different heterozygous MFN2 mutations, including 4 novel mutations, in 24 patients from 14 different Spanish families with CMT2A2. Six (42.8%) of 14 families carried the same mutation (R468H; 608507.0015). Overall, MFN2 mutations were identified in 16% of the total cohort of 85 Spanish families with axonal CMT, and Casasnovas et al. (2010) concluded that MFN2 is the most frequent cause of axonal CMT in this population. </p><p>In 2 British sibs with autosomal recessive inheritance of severe early-onset Charcot-Marie-Tooth disease-2A2B (CMT2A2B; 617087), Polke et al. (2011) identified compound heterozygosity for 2 mutations in the MFN2 gene (608507.0017-608507.0018). </p><p>Larrea et al. (2019) evaluated mitochondrial bioenergetics and mitochondrial-associated ER membrane (MAM) function in fibroblasts from 3 individuals with CMT2A2B and mutations in MFN2. The first individual (P1) was a 32-year-old woman with an R364W mutation (608507.0011) and a severe presentation, including onset of mobility and balance issues at age 2 years and 7 months. The second individual (P2) was a 62-year-old man with an M376V mutation who had mild clinical features and presented with weakness at age 11 years. The third individual (P3) was a 34-year-old woman with a W740S mutation (608507.0002) with a mild clinical presentation. Gene expression studies showed that steady-state levels of MFN2 mRNA were approximately 2-fold higher in patient fibroblasts compared to controls, and that mutant and wildtype alleles were expressed at essentially the same steady-state level in all 3 patient fibroblast lines. MFN2 protein levels were not different between patient and control fibroblasts. Mitochondrial morphology studies showed no difference between control and mutant mitochondrial perimeter or surface area, but patient cells showed a lower degree of physical association between the mitochondria and ER. An assessment of several measures of MAM function showed that, compared to controls, P3 fibroblasts had reduced serine incorporation in phosphatidylserine and phosphatidylethanolamine; P1 and P2 fibroblasts had increased cholesteryl ester synthesis; and P1 fibroblasts had significantly increased lipid droplets. Evaluation of calcium homeostasis showed only moderate and variable differences between patients and controls. Additionally, bioenergetic function, as measured by oxygen consumption studies, was not impaired in patient versus control cells. Larrea et al. (2019) concluded that differences in the characteristics of mitochondrial-ER communication resulting from individual MFN2 mutations may have different effects on MAM function. </p><p>Pipis et al. (2020) evaluated clinical and molecular findings in 196 individuals with CMT2A2A and CMT2A2B in a large multicenter prospective cohort study. One hundred and seventy-nine individuals from 133 families had dominant mutations, and 17 patients from 13 families had compound heterozygous (16 patients) or homozygous mutations (1 patient), in MFN2. The majority of mutations occurred in the dynamin-GTPase domain. Genetic variants at certain amino acid positions, including arg94, arg104, ser249, and trp740, were always pathogenic, with no evidence of reduced penetrance or variable expressivity. </p><p><strong><em>Multiple Symmetric Lipomatosis With or Without Axonal Peripheral Neuropathy</em></strong></p><p>
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In a 33-year-old woman (CMT40) with multiple symmetric lipomatosis (MSL; 151800) and early-onset severe axonal peripheral neuropathy, Nicholson et al. (2008) identified a homozygous missense mutation in the MFN2 gene (R707W; 608507.0013). Each parent was heterozygous for the mutation and showed mild features of a peripheral neuropathy, although they were not diagnosed with Charcot-Marie-Tooth disease. </p><p>In 2 brothers, born of consanguineous Irish parents, with MSL and late-onset axonal peripheral neuropathy, Sawyer et al. (2015) identified a homozygous R707W mutation in the MFN2 gene. The mutation, which was found by whole-exome sequencing, was not present in their unaffected sibs. In vitro expression studies in MFN2-null cells showed that the R707W mutant had a reduced capacity to tubulate mitochondria. In addition, mitochondria in mutant cells were prone to aggregation, were defective in forming homo-oligomers, and formed smaller oligomeric complexes compared to wildtype MFN2. </p><p>Carr et al. (2015) reported a 44-year-old patient (family 4) of UK origin with MSL and early-onset axonal peripheral neuropathy associated with compound heterozygous mutations in the MFN2 gene: an exon 7/8 deletion (608507.0018) and R707W. </p><p>In 3 patients (P2, P3, and P4) from 2 unrelated European families with MSL, Rocha et al. (2017) identified a homozygous R707W mutation in the MFN2 gene. Another patient with the disorder (P1) was compound heterozygous for R707W and arg343del (608507.0023). The mutations, which were found by exome sequencing or direct Sanger sequencing, segregated with the disorder in the families from whom parental DNA was available for study. Studies of abnormal adipose tissue showed hyperplasia of UCP1 (113730)-negative unilocular adipocytes and proliferation of round, enlarged mitochondria with fragmented cristae. Transcriptome analysis of adipose tissue showed perturbation of gene expression related to mitochondrial dysfunction and oxidative phosphorylation. There was also activation of genes related to cellular stress response pathways, including oxidative stress and unfolded protein response pathways, and upregulation of signatures related to tissue proliferation and survival. Examination of gene expression patterns identified the overgrown adipose tissue as white adipose tissue. In contrast, patient fibroblasts showed normal MFN2 expression and appropriate mitochondrial localization with normal mitochondria. These findings suggested that the abnormalities resulting from MFN2 mutations are tissue-specific. </p><p>In 6 patients from 5 families of French or Portuguese descent with MSL, Capel et al. (2018) identified a homozygous R707W mutation in the MFN2 gene. The patients were ascertained from a cohort of 66 individuals with altered fat distribution and lipomas who underwent sequencing of the MFN2 gene. Patient-derived lipomatous adipose tissue showed weak expression of the brown fat marker UCP1, and increased expression of thermogenic markers CITED1 (300149) and FGF21 (609436). Ultrastructural studies showed enlargement of the cytoplasmic ring of adipocytes and increased numbers of enlarged mitochondria with disorganized cristae or double membrane structures, suggestive of mitophagy. Gene expression studies of lipomatous tissue showed normal MFN2 expression and decreased expression of leptin and adiponectin. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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Using data from the platelet RNA and expression-1 (PRAX1) study, previous genomewide association studies (GWAS) of cardiovascular disease, and platelet-specific gene and allele-specific expression analysis in platelets from 154 normal individuals, Simon et al. (2016) identified rs1474868 in the MFN2 gene as a possible functional variant. This SNP drives expression of a platelet-specific alternative 5-prime start site, located in an unannotated human platelet-expressed exon termed 'exon 2b.' A noncoding variant in linkage disequilibrium with rs1474868, rs3766744, was identified as a regulator of MFN2 transcriptional activity, and platelet count and MFN2 expression were associated with allele dosage of the latter variant. The study linked rs1474868 to a platelet-specific regulatory role for MFN2 and provided some evidence for the hypothesis that increased platelet count may be a risk factor for cardiovascular disease. </p>
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</span>
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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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</h4>
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<span class="mim-text-font">
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<p>Chen et al. (2003) found that both Mfn1- and Mfn2-deficient mice died in midgestation. Whereas Mfn2 mutant embryos showed disruption of the placental trophoblast giant cell layer, Mfn1-deficient giant cells were normal. Embryonic fibroblasts lacking Mfn displayed fragmented mitochondria due to severe reduction in mitochondrial fusion. Mfn1 and Mfn2 formed homotypic and heterotypic complexes, and rescue of mutant cells indicated that the homotypic complexes were functional for fusion. A subset of mitochondria in mutant cells also lost membrane potential. The authors concluded that Mfn1 and Mfn2 have both redundant and distinct functions and act in 3 separate molecular complexes to promote mitochondrial fusion. </p><p>Detmer et al. (2008) generated transgenic mice expressing a pathogenic Mfn2 T105M mutation in peripheral motor neurons. Mutant mice developed key clinical features of CMT2A in a dose-dependent manner. Homozygous mice had a severe gait defect from birth due to an inability to dorsiflex the hindpaws, and they consequently dragged their hindpaws while walking and supported themselves on the hind knuckles, rather than the soles. Anterior calf muscles showed severe atrophy. There was decreased penetrance of the defects as well as lack of progression. Histologic studies showed reduced numbers of motor axons in the motor roots and improper mitochondrial distribution with tight clusters of mitochondria within axons. Homozygous mice had drastically short tails that were deformed, whereas heterozygous mice had shorter tails with mild to moderate bony kinks or thickening. </p><p>Fyfe et al. (2011) used genomewide linkage analysis followed by candidate gene sequencing to identify a homozygous 3-bp deletion in the canine Mfn2 gene as causative of a severe autosomal recessive form of fetal-onset neuroaxonal dystrophy. The in-frame 3-bp deletion was predicted to result in the deletion of a conserved glu539 residue. Mutant mRNA was expressed, but mutant protein was nearly undetectable on Western blot analysis of dog tissues. Immunohistochemical studies of normal pup brainstem showed robust granular cytoplasmic staining of Mfn2 in cerebellar Purkinje cells, deep cerebellar nuclei, and most large neurons in identified nuclei. The phenotype was characterized by death at birth due to respiratory failure. Affected fetuses had swollen axons/spheroids throughout the extrapyramidal motor system of the brainstem, spinal cord, and peripheral nerves, as well as cerebellar hypoplasia. Axonal swelling was composed of membrane-bound fragments of variably degenerated mitochondria and other tubulofilamentous material. The phenotype was reminiscent of human neuroaxonal dystrophy (256600) caused by mutation in the PLA2G6 gene (603604); however, brain iron accumulation was not observed in canines with the Mfn2 mutation. </p>
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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>23 Selected Examples):</strong>
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<h4>
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<span class="mim-font">
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<strong>.0001 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A</strong>
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</span>
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</h4>
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MFN2, ARG94GLN
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<br />
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SNP: rs28940291,
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gnomAD: rs28940291,
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ClinVar: RCV000002356, RCV000286431, RCV000463055, RCV000857091, RCV003332992, RCV003332993, RCV003343597
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<span class="mim-text-font">
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<p>In affected members of a Japanese kindred (family 693) with autosomal dominant Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260) originally reported by Saito et al. (1997) as well as in a Russian kindred with CMT2A2A, Zuchner et al. (2004) identified a heterozygous 281G-A transition in the MFN2 gene, resulting in an arg94-to-gln (R94Q) substitution in the predicted beginning of the GTPase domain of the protein. Age at disease onset in the 2 kindreds ranged from 3 to 17 years. A different mutation affecting the same codon (R94W; 608507.0009) was identified in another patient. </p><p>Casasnovas et al. (2010) identified a heterozygous R94Q mutation in affected members of a Spanish family with early-onset severe CMT2A2A and optic atrophy. </p>
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<h4>
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<span class="mim-font">
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<strong>.0002 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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MFN2, TRP740SER
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<br />
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SNP: rs28940292,
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ClinVar: RCV000002357, RCV000197403, RCV000235811, RCV000763240, RCV000857112, RCV001001747, RCV002426480, RCV002444413
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<span class="mim-text-font">
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<p>In affected members of a family with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260) originally reported by Ben Othmane et al. (1993), Zuchner et al. (2004) identified a heterozygous 2219G-C transversion in the MFN2 gene, resulting in a trp740-to-ser (W740S) substitution. Age at disease onset ranged from 5 to 52 years. </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>.0003 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A</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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MFN2, LEU76PRO
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<br />
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SNP: rs28940293,
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gnomAD: rs28940293,
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ClinVar: RCV000002358, RCV000200837, RCV000653847
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</span>
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</div>
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<span class="mim-text-font">
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<p>In affected members of a family with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260) originally reported by Pericak-Vance et al. (1997), Zuchner et al. (2004) identified a heterozygous 227T-C transition in the MFN2 gene, resulting in a leu76-to-pro (L76P) substitution. Age at disease onset ranged from 7 to 44 years. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0004 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A</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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MFN2, ARG280HIS
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<br />
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SNP: rs28940294,
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gnomAD: rs28940294,
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ClinVar: RCV000002359, RCV000236600, RCV000549934, RCV000789418, RCV001836692, RCV002468552
|
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|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In affected members of a family with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260) originally reported by Pericak-Vance et al. (1997), Zuchner et al. (2004) identified a heterozygous 839G-A transition in the MFN2 gene, resulting in an arg280-to-his (R280H) substitution. Age at disease onset ranged from 11 to 35 years. </p><p>Chung et al. (2006) reported a large multigenerational Korean family with late-onset CMT2A2A carrying a heterozygous R280H mutation. Onset ranged between 11 and 42 years, and affected individuals had mild muscle weakness and atrophy. Associated but variable features included pain, tremor, dysarthria, extensor plantar responses, and migraine. One patient had sensorineural hearing loss. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0005 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A</strong>
|
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</span>
|
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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MFN2, PRO251ALA
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<br />
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|
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SNP: rs28940295,
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ClinVar: RCV000002360, RCV000789417
|
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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 an Italian family with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260) originally reported by Muglia et al. (2001), Zuchner et al. (2004) identified a heterozygous 751C-G transversion in the MFN2 gene, resulting in a pro251-to-ala (P251A) substitution. Age at disease onset ranged from 8 to 50 years. </p>
|
|
</span>
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|
</div>
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<div>
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<br />
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|
</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
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<span class="mim-text-font">
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|
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|
MFN2, VAL69PHE
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<br />
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|
|
SNP: rs28940296,
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|
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|
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gnomAD: rs28940296,
|
|
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|
|
|
ClinVar: RCV000002361
|
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Turkish family with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260), Zuchner et al. (2004) identified a heterozygous c.205G-T transversion in the MFN2 gene, resulting in a val69-to-phe (V69F) substitution. Age at disease onset ranged from 5 to 15 years. The family had previously been reported by Bissar-Tadmouri et al. (2004). </p>
|
|
</span>
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|
</div>
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<div>
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<br />
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|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
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|
MFN2, LYS357ASN
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|
|
<br />
|
|
|
|
SNP: rs119103261,
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|
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|
|
|
ClinVar: RCV000002362, RCV000547064, RCV005003317
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260), Kijima et al. (2005) identified an apparently de novo missense mutation, lys357 to asn (K357N), resulting from a heterozygous G-to-C transversion at nucleotide 1071 of the MFN2 gene. </p>
|
|
</span>
|
|
</div>
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|
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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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MFN2, HIS165ASP
|
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|
|
|
<br />
|
|
|
|
SNP: rs119103262,
|
|
|
|
|
|
|
|
ClinVar: RCV000002363, RCV000789416, RCV001208639
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 11 affected members of a family (CMT66) with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260), Zhu et al. (2005) identified a heterozygous 493C-G transversion in exon 6 of the MFN2 gene, resulting in a his165-to-asp (H165D) substitution in the conserved GTPase domain. The family was previously reported by Vucic et al. (2003) as having CMT with pyramidal features. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
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<br />
|
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</div>
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|
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</div>
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|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
NEUROPATHY, HEREDITARY MOTOR AND SENSORY, TYPE VIA, INCLUDED
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MFN2, ARG94TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs119103263,
|
|
|
|
|
|
|
|
ClinVar: RCV000002364, RCV000190245, RCV000199279, RCV000200468, RCV000415132, RCV001173686, RCV003162206, RCV004558234, RCV004558235
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with early-onset Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260), Zuchner et al. (2004) identified a heterozygous 280C-T transition in exon 4 of the MFN2 gene, resulting in an arg94-to-trp (R94W) substitution. A different mutation affecting the same codon (R94Q; 608507.0001) was identified in another family. </p><p>Zuchner et al. (2006) identified a heterozygous R94W mutation in an African American mother and daughter with hereditary motor and sensory neuropathy with optic atrophy (HMSN6A; 601152). Both patients had early onset of axonal neuropathy, at ages 8 and 3 years, respectively, and late onset of optic atrophy, at ages 50 and 40 years, respectively. </p><p>Chung et al. (2006) identified a heterozygous R94W mutation in 2 Korean families with severe early-onset CMT2A2A and no evidence of optic atrophy. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 NEUROPATHY, HEREDITARY MOTOR AND SENSORY, TYPE VIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MFN2, GLN276ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs119103264,
|
|
|
|
|
|
|
|
ClinVar: RCV000002366, RCV001253214, RCV002426481, RCV003482223
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a woman with hereditary motor and sensory neuropathy type VIA (HMSN6A; 601152), Zuchner et al. (2006) identified a heterozygous 827A-G transition in exon 9 of the MFN2 gene, resulting in a gln276-to-arg (Q276R) substitution. The patient's mother and sister both carried the mutation, but only had peripheral neuropathy without optic atrophy. Zuchner et al. (2006) suggested incomplete penetrance. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 NEUROPATHY, HEREDITARY MOTOR AND SENSORY, TYPE VIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MFN2, ARG364TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs119103265,
|
|
|
|
|
|
|
|
ClinVar: RCV000002367, RCV000023711, RCV000195560, RCV000198024, RCV000857103, RCV000857104
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and 2 sons with hereditary motor and sensory neuropathy type VIA (HMSN6A; 601152), Zuchner et al. (2006) identified a heterozygous 1090C-T transition in exon 11 of the MFN2 gene, resulting in an arg364-to-trp (R364W) substitution. All patients had a severe form of the disorder with neuropathy developing by age 1 year and optic atrophy by age 10 years. </p><p>Chung et al. (2006) reported 4 unrelated Korean families with early-onset neuropathy before 10 years of age and a heterozygous R364W mutation. In 1 family, only 1 of 3 mutation carriers had optic atrophy. In another family, both mutation carriers had optic atrophy. Optic atrophy was not present in the remaining 2 families, more consistent with a diagnosis of Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260). All except 1 patient had scoliosis and most had contractures. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
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</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 NEUROPATHY, HEREDITARY MOTOR AND SENSORY, TYPE VIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MFN2, THR206ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs119103266,
|
|
|
|
|
|
|
|
ClinVar: RCV000002368, RCV000857095, RCV001268502
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and son with hereditary motor and sensory neuropathy type VIA (HMSN6A; 601152), Zuchner et al. (2006) identified a heterozygous 617C-T transition in exon 7 of the MFN2 gene, resulting in a thr206-to-ile (T206I) substitution. </p>
|
|
</span>
|
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</div>
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<div>
|
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<br />
|
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</div>
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|
|
</div>
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<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 LIPOMATOSIS, MULTIPLE SYMMETRIC, WITH OR WITHOUT AXONAL PERIPHERAL NEUROPATHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2B, AUTOSOMAL RECESSIVE, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MFN2, ARG707TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs119103267,
|
|
|
|
|
|
gnomAD: rs119103267,
|
|
|
|
|
|
ClinVar: RCV000002369, RCV000199654, RCV000239892, RCV000472857, RCV000624830, RCV000778183, RCV001173687, RCV001775061, RCV002247240, RCV002285136, RCV002476912, RCV002508915, RCV003231070, RCV003319157
|
|
|
|
|
|
</span>
|
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</div>
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Multiple Symmetric Lipomatosis With or Without Axonal Peripheral Neuropathy</em></strong></p><p>
|
|
In a 33-year-old woman (CMT40) with multiple symmetric lipomatosis (MSL; 151800) and early-onset severe axonal peripheral neuropathy, Nicholson et al. (2008) identified a homozygous c.2119C-T transition in the MFN2 gene, resulting in an arg707-to-trp (R707W) substitution at a highly conserved residue. Each parent was heterozygous for the mutation and showed mild features of a peripheral neuropathy, although they were not diagnosed with the disease. </p><p>In 2 brothers (patients 1 and 2), born of consanguineous Irish parents, with MSL and mild axonal peripheral neuropathy, Sawyer et al. (2015) identified a homozygous c.2119C-T transition (c.2119C-T, NM_001127660) in exon 17 of the MFN2 gene. The mutation, which was found by whole-exome sequencing, was not present in their unaffected sibs. The mutation occurred within the heptad repeat 2 domain at the C terminal of MFN2, which is though to permit homotypic interactions and heterotypic binding to MFN1 (608506). It was found in the heterozygous state at a low frequency in the ExAC database (frequency of 0.0003). In vitro expression studies in MFN2-null cells showed that the R707W mutant had a reduced capacity to tubulate mitochondria. In addition, mitochondria in mutant cells were prone to aggregation, were defective in forming homooligomers, and formed smaller oligomeric complexes compared to wildtype MFN2. </p><p>Carr et al. (2015) reported a 44-year-old woman (patient 4) of UK ancestry with MSL and early-onset axonal neuropathy who was compound heterozygous for 2 mutations in the MFN2 gene: an exon 7-8 deletion (608507.0018) and R707W. </p><p>In 3 patients (P2, P3, and P4) from 2 unrelated European families with MSL, Rocha et al. (2017) identified a homozygous R707W mutation in the MFN2 gene. Another patient with the disorder (P1) was compound heterozygous for R707W and arg343del (608507.0023). The mutations, which were found by exome sequencing or direct Sanger sequencing, segregated with the disorder in the families from whom parental DNA was available for study. P1 and P4 showed evidence of a peripheral neuropathy, whereas sibs P2 and P3 did not. Studies of abnormal adipose tissue showed hyperplasia of UCP1 (113730)-negative unilocular adipocytes and proliferation of round, enlarged mitochondria with fragmented cristae. Transcriptome analysis of adipose tissue showed perturbation of gene expression related to mitochondrial dysfunction and oxidative phosphorylation. There was also alteration of genes related to cellular stress response pathways, including oxidative stress and unfolded protein response pathways, and upregulation of signatures related to tissue proliferation and survival. Examination of gene expression patterns identified the overgrown adipose tissue as white adipose tissue. In contrast, patient fibroblasts showed normal MFN2 expression and appropriate mitochondrial localization with normal mitochondria. These findings suggested that the abnormalities resulting from MFN2 mutations are tissue-specific. </p><p>In 6 adult patients from 5 European families with MSL and axonal peripheral neuropathy, Capel et al. (2018) identified a homozygous R707W mutation in the MFN2 gene. Patient-derived lipomatous adipose tissue showed weak expression of the brown fat marker UCP1, and increased expression of thermogenic markers CITED1 (300149) and FGF21 (609436). Ultrastructural studies showed enlargement of the cytoplasmic ring of adipocytes and increased numbers of enlarged mitochondria with disorganized cristae or double membrane structures, suggestive of mitophagy. Gene expression studies of lipomatous tissue showed normal MFN2 expression and decreased expression of leptin and adiponectin. UCP1 expression was decreased, and CITED1 and FGF21 expression were increased. </p><p><strong><em>Charcot-Marie-Tooth Disease 2A2B</em></strong></p><p>
|
|
In 3 sibs (patients 6-8) with autosomal recessive inheritance of severe early-onset Charcot-Marie-Tooth disease-2A2B (CMT2A2B; 617087), Calvo et al. (2009) identified compound heterozygous missense mutations in the MFN2 gene: R707W and a c.322G-A transition in exon 5, resulting in a gly108-to-arg (G108R; 608507.0022) substitution in the GTPase domain. The patients, who were 19, 24, and 25 years of age, were not noted to have lipomatosis. Each of their unaffected parents was heterozygous for 1 of the mutations. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 NEUROPATHY, HEREDITARY MOTOR AND SENSORY, TYPE VIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MFN2, ARG104TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs119103268,
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|
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|
|
ClinVar: RCV000002370, RCV000002371, RCV000144872, RCV000197230, RCV000515385, RCV000556047, RCV001267430, RCV003332994, RCV003332995
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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 an Italian father and 2 sons with peripheral neuropathy, Del Bo et al. (2008) identified a heterozygous c.310C-T transition in exon 4 of the MFN2 gene, resulting in an arg104-to-trp (R104W) substitution at a highly conserved residue in the GTPase domain. The phenotype was highly variable within the family. The father had a symmetric axonal, predominantly motor polyneuropathy, spastic gait, and pes cavus, consistent with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260), as well as impaired nocturnal vision and sensorineural hearing loss, consistent with hereditary motor and sensory neuropathy type VIA (HMSN6A; 601152). He also showed cognitive decline first noted in his forties. Both sons had delayed motor and language development, decreased IQ, steppage gait, distal muscle weakness and atrophy, and axonal sensorimotor neuropathy at ages 10 and 7 years, respectively. One son also had optic nerve dysfunction. MR spectroscopy (MRS) in the father suggested a defect in mitochondrial energy metabolism in the occipital cortex. Del Bo et al. (2008) suggested that central nervous system involvement and cognitive impairment may be other phenotypic features of MFN2 mutations. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0015 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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MFN2, ARG468HIS
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<br />
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SNP: rs138382758,
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gnomAD: rs138382758,
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ClinVar: RCV000002372, RCV000196650, RCV000312138, RCV000487518, RCV001086652, RCV001172693, RCV001814957, RCV002390086, RCV004814803, RCV004814804
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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>Casasnovas et al. (2010) identified a heterozygous 1403G-A transition in exon 14 of the MFN2 gene, resulting in an arg468-to-his (R468H) substitution, in affected members of 6 (42.8%) of 14 unrelated Spanish families with autosomal dominant Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260). All patients with the R468H mutation had either mild or moderate disease that presented late in adult life in the third to fifth decade. Fibroblasts from 1 patient with the R468H mutation showed a mitochondrial coupling defect, a 50% decrease in ATP production, and an increase of the respiration rate linked to complex II. </p>
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|
</span>
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|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A</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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MFN2, IVS13DS, T-C, +2
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<br />
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|
|
SNP: rs111723244,
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|
|
ClinVar: RCV000023713, RCV000789373
|
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</span>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In 3 sibs with a severe form of adult-onset Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 608260) who all developed a fatal subacute encephalopathy, Boaretto et al. (2010) identified a heterozygous T-to-C transition (1392+2T-C) in intron 13 of the MFN2 gene. Their father had died at age 61 of a similar disorder. The mutation was not found in 200 control chromosomes, but was present in an unaffected 64-year-old sister, indicating incomplete penetrance. RT-PCR analysis showed that the splice site mutation resulted in 4 aberrant MFN2 transcripts and completely abolished correct splicing of exon 13. There were different splicing patterns in the cell lines, suggesting that activation of cryptic splice sites may be under control of tissue-specific factors. Boaretto et al. (2010) noted the unusual encephalopathy present in this family, and suggested that the nature of the mutation may have put sensitive areas of the brain in a precarious energetic equilibrium. However, unknown genetic, epigenetic factors, or environmental factors likely played a role in the phenotype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2B, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
MFN2, PHE216SER
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|
<br />
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SNP: rs387906990,
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|
|
gnomAD: rs387906990,
|
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|
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|
|
ClinVar: RCV000023714, RCV000235670, RCV000456775
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 British sibs with autosomal recessive inheritance of severe early-onset Charcot-Marie-Tooth disease-2A2B (CMT2A2B; 617087), Polke et al. (2011) identified compound heterozygosity for 2 mutations in the MFN2 gene: a 647T-C transition in exon 7, resulting in a phe216-to-ser (F216S) substitution on the maternal allele, and a deletion of exons 7 and 8 (608507.0018) on the paternal allele. Transcript analysis showed low levels of a shortened transcript from the paternal allele, in which exon 6 was spliced to exon 9, suggested that some of the mutant transcript was subject to nonsense-mediated mRNA decay. If translated, the deletion transcript would result in a truncated out-of-frame protein lacking several important domains. Thus, it could represent either a null mutation or have a dominant-negative effect with reduced penetrance if coexpressed with a normal allele. The patients had onset at 12 and 18 months, respectively, of foot drop associated with marked upper and lower limb muscle weakness. Pinprick sensation was decreased, whereas vibration sense was basically preserved. One patient had optic atrophy and the other had pale optic disc; both were wheelchair-bound later in childhood. Each parent was clinically unaffected. </p>
|
|
</span>
|
|
</div>
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|
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<div>
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|
<br />
|
|
</div>
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</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2B, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
LIPOMATOSIS, MULTIPLE SYMMETRIC, WITH AXONAL PERIPHERAL NEUROPATHY, INCLUDED
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MFN2, EX7-8DEL
|
|
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|
|
|
<br />
|
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|
|
|
|
ClinVar: RCV000023715, RCV003231109
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the deletion of exons 7 and 8 in the MFN2 gene that was found in compound heterozygous state in 2 sibs of British descent with autosomal recessive inheritance of severe early-onset Charcot-Marie-Tooth disease-2A2B (CMT2A2B; 609260) by Polke et al. (2011), see 608507.0017. </p><p>Carr et al. (2015) reported 3 additional patients of UK ancestry with autosomal recessive early-onset axonal CMT2A2B due to compound heterozygous mutations in the MFN2 gene. All patients carried the exon 7-8 deletion on 1 allele, and haplotype analysis of these patients and the sibs reported by Polke et al. (2011) indicated a founder effect in this population. Two of the patients (families 2 and 3) carried a T362M (608507.0019) mutation on the other allele. The patient in family 4, who had multiple symmetric lipomatosis (MSL; 151800) with axonal peripheral neuropathy, carried a R707W (608507.0013) mutation on the other allele. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
|
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2B, AUTOSOMAL RECESSIVE, INCLUDED
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MFN2, THR362MET
|
|
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|
<br />
|
|
|
|
SNP: rs387906991,
|
|
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|
|
|
gnomAD: rs387906991,
|
|
|
|
|
|
ClinVar: RCV000023716, RCV000240513, RCV000857102, RCV001198485, RCV001388766, RCV002415428, RCV002472935
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Korean mother and daughter with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260), Chung et al. (2006) identified a heterozygous 1085C-T transition in the MFN2 gene, resulting in a thr362-to-met (T362M) substitution. The patients had late onset and a mild phenotype. </p><p>In 2 adult Italian sibs with autosomal recessive inheritance of severe early-onset CMT2A2B (617087), Polke et al. (2011) identified compound heterozygosity for 2 mutations in the MFN2 gene: a T362M substitution on the maternal allele, and a 3-bp in-frame deletion (113delAGA; 608507.0020) resulting in a deletion of lys38 (lys38del), presumably from the paternal allele, although no DNA was available from the deceased father. The patients had onset of foot drop and upper and lower limb weakness at age 3 years. They also had decreased pinprick and vibration senses, more severe in the lower limbs, kyphosis, pale optic discs, visual loss, severe facial weakness, and respiratory muscle weakness. One had hearing loss and vocal cord palsy. Both were wheelchair-bound. Nerve conduction studies showed absence of nerve conduction in 1 patient tested. Neither parent was affected. Polke et al. (2011) noted that the T362M mutation had also been reported in families with dominant transmission, suggesting that it has a dominant-negative effect; the pathogenic effect of the lys38 deletion mutation was unknown, although it was not found in 550 control chromosomes. </p><p>In a 32-year-old woman (CMT742) with autosomal recessive CMT2A2B, Nicholson et al. (2008) identified compound heterozygosity for 2 missense mutations in the MFN2 gene: T362M and A164V (608507.0021). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2B, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MFN2, 3-BP DEL, 113AGA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1478175861,
|
|
|
|
|
|
|
|
ClinVar: RCV000023712, RCV000790039, RCV001288126, RCV005089307
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 3-bp deletion in the MFN2 gene (113delAGA) that was found in compound heterozygous state in patients with autosomal recessive inheritance of severe early-onset Charcot-Marie-Tooth disease-2A2B (CMT2A2B; 617087) by Polke et al. (2011), see 608507.0019. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2B, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MFN2, ALA164VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1553142699,
|
|
|
|
|
|
|
|
ClinVar: RCV000664056, RCV000790032
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 32-year-old woman (CMT742) with autosomal recessive early-onset Charcot-Marie-Tooth disease-2A2B (CMT2A2B; 617087), Nicholson et al. (2008) identified compound heterozygous missense mutations in the MFN2 gene: a c.491C-T transition, resulting in an ala164-to-val (A164V) substitution, and a c.1085C-T transition, resulting in a thr362-to-met (T362M; 608507.0019) substitution. The patient had onset of symptoms at 3 years of age. She had delayed motor development and was wheelchair-bound at age 10. Other features included mild deafness, scoliosis, and high-pitched voice. Her parents, who were each heterozygous for one of the mutations, showed mild features of the disorder, including pes cavus and inability to heel-walk. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
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|
<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
|
|
|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2B, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MFN2, GLY108ARG
|
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|
|
|
|
<br />
|
|
|
|
SNP: rs1569829573,
|
|
|
|
|
|
|
|
ClinVar: RCV000790317, RCV003234565
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.322G-A transition in exon 5 of the MFN2 gene, resulting in a gly108-to-arg (G108R) substitution, that was found in compound heterozygous state in 3 sibs with autosomal recessive inheritance of severe early-onset Charcot-Marie-Tooth disease-2A2B (CMT2A2B; 617087) by Calvo et al. (2009), see 608507.0013. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 LIPOMATOSIS, MULTIPLE SYMMETRIC, WITH AXONAL PERIPHERAL NEUROPATHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MFN2, 3-BP DEL, ARG343DEL
|
|
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|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV003232881
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the in-frame 3-bp deletion in the MFN2 gene, resulting in the deletion of residue arg343 (arg343del), that was found in compound heterozygous state in a patient with multiple symmetric lipomatosis with axonal peripheral neuropathy (MSL; 151800) by Rocha et al. (2017), see 608507.0013. </p>
|
|
</span>
|
|
</div>
|
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|
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|
<div>
|
|
<br />
|
|
</div>
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</div>
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</div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
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|
<div>
|
|
<ol>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bach, D., Pich, S., Soriano, F. X., Vega, N., Baumgartner, B., Oriola, J., Daugaard, J. R., Lloberas, J., Camps, M., Zierath, J. R., Rabasa-Lhoret, R., Wallberg-Henriksson, H., Laville, M., Palacin, M., Vidal, H., Rivera, F., Brand, M., Zorzano, A.
|
|
<strong>Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism: a novel regulatory mechanism altered in obesity.</strong>
|
|
J. Biol. Chem. 278: 17190-17197, 2003.
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|
|
[PubMed: 12598526]
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|
[Full Text: https://doi.org/10.1074/jbc.M212754200]
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</p>
|
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</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Ben Othmane, K., Middleton, L. T., Loprest, L. J., Wilkinson, K. M., Lennon, F., Rozear, M. P., Stajich, J. M., Gaskell, P. C., Roses, A. D., Pericak-Vance, M. A., Vance, J. M.
|
|
<strong>Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity.</strong>
|
|
Genomics 17: 370-375, 1993.
|
|
|
|
|
|
[PubMed: 8406488]
|
|
|
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|
|
[Full Text: https://doi.org/10.1006/geno.1993.1334]
|
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|
</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Bissar-Tadmouri, N., Nelis, E., Zuchner, S., Parman, Y., Deymeer, F., Serdaroglu, P., De Jonghe, P., Van Gerwen, V., Timmerman, V., Schroder, J. M., Battaloglu, E.
|
|
<strong>Absence of KIF1B mutation in a large Turkish CMT2A family suggests involvement of a second gene.</strong>
|
|
Neurology 62: 1522-1525, 2004.
|
|
|
|
|
|
[PubMed: 15136675]
|
|
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|
|
[Full Text: https://doi.org/10.1212/01.wnl.0000123253.57555.3a]
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|
</p>
|
|
</li>
|
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<li>
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Sawyer, S. L., Cheuk-Him Ng, A., Innes, A. M., Wagner, J. D., Dyment, D. A., Tetreault, M., Care4Rare Canada Consortium, Majewski, J., Boycott, K. M., Screaton, R. A., Nicholson, G.
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Simon, L. M., Chen, E. S., Edelstein, L. C., Kong, X., Bhatlekar, S., Rigoutsos, I., Bray, P. F., Shaw, C. A.
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Vadnais, M. L., Lin, A. M., Gerton, G. L.
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<strong>Mitochondrial fusion protein MFN2 interacts with the mitostatin-related protein MNS1 required for mouse sperm flagellar structure and function.</strong>
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Zhu, D., Kennerson, M. L., Walizada, G., Zuchner, S., Vance, J. M., Nicholson, G. A.
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<strong>Charcot-Marie-Tooth with pyramidal signs is genetically heterogeneous: families with and without MFN2 mutations.</strong>
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Zuchner, S., De Jonghe, P., Jordanova, A., Claeys, K. G., Guergueltcheva, V., Cherninkova, S., Hamilton, S. R., Van Stavern, G., Krajewski, K. M., Stajich, J., Tournev, I., Verhoeven, K., Langerhorst, C. T., de Visser, M., Baas, F., Bird, T., Timmerman, V., Shy, M., Vance, J. M.
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<strong>Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2.</strong>
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<strong>Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.</strong>
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Cassandra L. Kniffin - updated : 05/26/2023<br>Hilary J. Vernon - updated : 03/29/2021<br>Hilary J. Vernon - updated : 10/20/2020<br>Bao Lige - updated : 08/28/2020<br>Ada Hamosh - updated : 10/09/2019<br>Ada Hamosh - updated : 09/27/2019<br>Ada Hamosh - updated : 05/29/2018<br>Ada Hamosh - updated : 12/14/2016<br>Cassandra L. Kniffin - updated : 08/24/2016<br>Cassandra L. Kniffin - updated : 6/14/2016<br>Ada Hamosh - updated : 1/31/2014<br>Ada Hamosh - updated : 5/29/2013<br>Cassandra L. Kniffin - updated : 3/11/2013<br>Cassandra L. Kniffin - updated : 11/2/2011<br>Cassandra L. Kniffin - updated : 6/20/2011<br>Cassandra L. Kniffin - updated : 3/22/2011<br>Cassandra L. Kniffin - updated : 5/27/2010<br>Cassandra L. Kniffin - updated : 3/1/2010<br>Cassandra L. Kniffin - updated : 1/11/2010<br>Cassandra L. Kniffin - updated : 3/16/2009<br>Ada Hamosh - updated : 1/6/2009<br>Patricia A. Hartz - updated : 10/29/2008<br>Cassandra L. Kniffin - updated : 9/25/2008<br>George E. Tiller - updated : 6/5/2008<br>Ada Hamosh - updated : 10/24/2006<br>Cassandra L. Kniffin - updated : 4/11/2006<br>Cassandra L. Kniffin - updated : 11/10/2005<br>Victor A. McKusick - updated : 2/21/2005<br>Cassandra L. Kniffin - updated : 1/31/2005<br>Cassandra L. Kniffin - updated : 4/5/2004
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