5309 lines
443 KiB
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5309 lines
443 KiB
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Entry
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- *606598 - GANGLIOSIDE-INDUCED DIFFERENTIATION-ASSOCIATED PROTEIN 1; GDAP1
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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">*606598</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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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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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/606598">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<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=ENSG00000104381;t=ENST00000220822" 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=54332" 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=606598" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000104381;t=ENST00000220822" 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_001040875,NM_001362929,NM_001362930,NM_001362931,NM_001362932,NM_018972,XM_017013586,XM_047421902" 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_018972" 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=606598" 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=05963&isoform_id=05963_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/GDAP1" 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/3378206,19354218,108773797,108773799,119607438,119607439,158258581,194380662,269849682,320461572,320461574,320461577,1370512500,1386635257,1386635261,1386635270,1386635307,2217372341,2462619938,2462619940" 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/Q8TB36" 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=54332" 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=ENSG00000104381;t=ENST00000220822" 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=GDAP1" 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=GDAP1" 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+54332" 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/GDAP1" 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:54332" 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/54332" 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=chr8&hgg_gene=ENST00000220822.12&hgg_start=74350403&hgg_end=74488872&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:15968" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=606598[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=606598[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/GDAP1/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/ENSG00000104381" 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=GDAP1" 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=GDAP1" 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=GDAP1" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://gdap1.mitodyn.org" title="MITOchondrial DYNamics variation pages" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">MITOchondrial DYNamics var…</a></div><div style="margin-left: 0.5em;"><a href="http://www.molgen.ua.ac.be/CMTMutations/" title="Inherited Peripheral Neuropathies Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Inherited Peripheral Neuro…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=GDAP1&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/PA28626" 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:15968" 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/FBgn0035587.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:1338002" 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/GDAP1#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:1338002" 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/54332/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=54332" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-050522-424" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=GDAP1&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> 715796006, 719512003, 725047007<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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606598
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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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GANGLIOSIDE-INDUCED DIFFERENTIATION-ASSOCIATED PROTEIN 1; GDAP1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=GDAP1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GDAP1</a></em></strong>
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: <a href="/geneMap/8/351?start=-3&limit=10&highlight=351">8q21.11</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr8:74350403-74488872&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'})">8:74,350,403-74,488,872</a> </span>
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</em>
|
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
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Location
|
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</th>
|
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<th>
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Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=607831,607706,608340,214400" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
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|
</th>
|
|
<th>
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|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
|
</tr>
|
|
</thead>
|
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<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/8/351?start=-3&limit=10&highlight=351">
|
|
8q21.11
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Charcot-Marie-Tooth disease, axonal, type 2K
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/607831"> 607831 </a>
|
|
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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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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<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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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Charcot-Marie-Tooth disease, axonal, with vocal cord paresis
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/607706"> 607706 </a>
|
|
|
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</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<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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</tr>
|
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|
|
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Charcot-Marie-Tooth disease, recessive intermediate, A
|
|
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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<p>The GDAP1 gene encodes a protein expressed in the central and peripheral nervous system, particularly in Schwann cells. GDAP1 is an integral membrane protein of the outer mitochondrial membrane (<a href="#16" class="mim-tip-reference" title="Niemann, A., Ruegg, M., La Padula, V., Schenone, A., Suter, U. <strong>Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease.</strong> J. Cell Biol. 170: 1067-1078, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16172208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16172208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16172208[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.200507087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16172208">Niemann et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16172208" 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>Gangliosides, sialic acid-containing glycosphingolipids, are abundant in brain tissue, and GD3 synthase (SIAT8; <a href="/entry/601123">601123</a>) plays a key role in their biosynthesis. Using differential display PCR to identify cDNAs induced at different time points by GD3 synthase expression in a mouse neuroblastoma cell line, <a href="#14" class="mim-tip-reference" title="Liu, H., Nakagawa, T., Kanematsu, T., Uchida, T., Tsuji, S. <strong>Isolation of 10 differentially expressed cDNAs in differentiated Neuro2a cells induced through controlled expression of the GD3 synthase gene.</strong> J. Neurochem. 72: 1781-1790, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10217254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10217254</a>] [<a href="https://doi.org/10.1046/j.1471-4159.1999.0721781.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10217254">Liu et al. (1999)</a> obtained cDNAs encoding 10 Gdap proteins, including Gdap1. The deduced 358-amino acid human GDAP1 protein is 94% identical to the mouse protein, with most divergence at the N terminus. Northern blot analysis revealed expression of a 4.1-kb Gdap1 transcript restricted to mouse brain tissue. Immunofluorescence microscopy demonstrated cytoplasmic expression in mouse cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10217254" 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="Pedrola, L., Espert, A., Wu, X., Claramunt, R., Shy, M. E., Palau, F. <strong>GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria.</strong> Hum. Molec. Genet. 14: 1087-1094, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15772096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15772096</a>] [<a href="https://doi.org/10.1093/hmg/ddi121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15772096">Pedrola et al. (2005)</a> stated that GDAP1 contains 2 N-terminal GST domains and 2 C-terminal transmembrane domains. Real-time PCR of adult rat tissues detected highest expression in spinal cord, dorsal root ganglia, and brain, with low expression in sciatic nerve, and no expression in liver or muscle. GDAP1 localized to the mitochondria in a human neuroblastoma cell line and in COS-7 cells. Western blot analysis of subcellular fractions with anti-GDAP1 antibody detected a 40-kD band corresponding to GDAP1 and an 88-kD band, suggesting that GDAP1 forms a homodimer. The C-terminal transmembrane domains were necessary for correct localization in mitochondria; however, missense mutations did not alter mitochondrial localization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15772096" 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="Cuesta, A., Pedrola, L., Sevilla, T., Garcia-Planells, J., Chumillas, M. J., Mayordomo, F., LeGuern, E., Marin, I., Vilchez, J. J., Palau, F. <strong>The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease.</strong> Nature Genet. 30: 22-24, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11743580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11743580</a>] [<a href="https://doi.org/10.1038/ng798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11743580">Cuesta et al. (2002)</a> determined that the GDAP1 gene contains 6 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11743580" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#22" class="mim-tip-reference" title="Xin, B., Puffenberger, E., Nye, L., Wiznitzer, M., Wang, H. <strong>A novel mutation in the GDAP1 gene is associated with autosomal recessive Charcot-Marie-Tooth disease in an Amish family.</strong> Clin. Genet. 74: 274-278, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18492089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18492089</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.01018.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18492089">Xin et al. (2008)</a> noted that the GDAP1 gene maps to chromosome 8q13.1-q21.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18492089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 8/27/2013."None>Gross (2013)</a> mapped the GDAP1 gene to chromosome 8q21.11 based on an alignment of the GDAP1 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC024939" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC024939</a>) with the genomic sequence (GRCh37).</p>
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<p>The GDAP1 gene may be involved in a signal transduction pathway in neuronal development. By Northern blot analysis, <a href="#8" class="mim-tip-reference" title="Cuesta, A., Pedrola, L., Sevilla, T., Garcia-Planells, J., Chumillas, M. J., Mayordomo, F., LeGuern, E., Marin, I., Vilchez, J. J., Palau, F. <strong>The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease.</strong> Nature Genet. 30: 22-24, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11743580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11743580</a>] [<a href="https://doi.org/10.1038/ng798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11743580">Cuesta et al. (2002)</a> showed greatest GDAP1 expression in whole brain and spinal cord. Amplification of human sural nerve and mouse sciatic nerve transcripts suggested that GDAP1 expression does not occur just in neurons but also in Schwann cells. However, GDAP1 expression is higher in central tissues than in peripheral nerves. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11743580" 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="Niemann, A., Ruegg, M., La Padula, V., Schenone, A., Suter, U. <strong>Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease.</strong> J. Cell Biol. 170: 1067-1078, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16172208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16172208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16172208[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.200507087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16172208">Niemann et al. (2005)</a> demonstrated that Gdap1 was expressed in both Schwann cells and neurons of rat peripheral nerve, as well as in various regions of the central nervous system. Subcellular localization studies showed that Gdap1 is an integral membrane protein of the outer mitochondrial membrane. Overexpression of Gdap1 induced fragmentation of mitochondria without inducing apoptosis, affecting overall mitochondrial activity, or interfering with mitochondrial fusion. The mitochondrial fusion proteins, mitofusin-1 (MFN1; <a href="/entry/608506">608506</a>) and -2 (MFN2; <a href="/entry/608507">608507</a>) and Drp1 (<a href="/entry/603850">603850</a>) were able to counterbalance these effects. Gdap1-specific knockdown by RNA interference resulted in a tubular mitochondrial morphology. <a href="#16" class="mim-tip-reference" title="Niemann, A., Ruegg, M., La Padula, V., Schenone, A., Suter, U. <strong>Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease.</strong> J. Cell Biol. 170: 1067-1078, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16172208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16172208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16172208[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.200507087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16172208">Niemann et al. (2005)</a> concluded that GDAP1 regulates mitochondrial dynamics that are critical for the proper function of myelinated peripheral nerves. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16172208" 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="Pedrola, L., Espert, A., Wu, X., Claramunt, R., Shy, M. E., Palau, F. <strong>GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria.</strong> Hum. Molec. Genet. 14: 1087-1094, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15772096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15772096</a>] [<a href="https://doi.org/10.1093/hmg/ddi121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15772096">Pedrola et al. (2005)</a> found that GST-activity assay detected no activity for soluble GDAP1. <a href="#20" class="mim-tip-reference" title="Shield, A. J., Murray, T. P., Board, P. G. <strong>Functional characterisation of ganglioside-induced differentiation-associated protein 1 as a glutathione transferase.</strong> Biochem. Biophys. Res. Commun. 347: 859-866, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16857173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16857173</a>] [<a href="https://doi.org/10.1016/j.bbrc.2006.06.189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16857173">Shield et al. (2006)</a> confirmed that the GDAP1 protein does not have glutathione transferase activity, although it appears to be structurally related to other cytosolic glutathione S-transferases (GST). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16857173+15772096" 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 4 different Tunisian families with Charcot-Marie-Tooth disease type 4A (CMT4A; <a href="/entry/214400">214400</a>), an autosomal recessive form of demyelinating peripheral neuropathy mapping to chromosome 8, <a href="#1" class="mim-tip-reference" title="Baxter, R. V., Ben Othmane, K., Rochelle, J. M., Stajich, J. E., Hulette, C., Dew-Knight, S., Hentati, F., Ben Hamida, M., Bel, S., Stenger, J. E., Gilbert, J. R., Pericak-Vance, M. A., Vance, J. M. <strong>Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21.</strong> Nature Genet. 30: 21-22, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11743579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11743579</a>] [<a href="https://doi.org/10.1038/ng796" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11743579">Baxter et al. (2002)</a> found homozygosity for 2 nonsense mutations and 1 missense mutation in the GDAP1 gene (W31X, <a href="#0001">606598.0001</a>; S194X, <a href="#0002">606598.0002</a>; R161H, <a href="#0003">606598.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11743579" 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 Spanish families reported by <a href="#19" class="mim-tip-reference" title="Sevilla, T., Cuesta, A., Chumillas, M. J., Mayordomo, F., Garcia-Planells, J., Palau, F., Vilchez, J. J. <strong>Clinical and genetic studies in three Spanish families with severe autosomal recessive Charcot-Marie-Tooth axonal neuropathy.</strong> Acta Myol. 20: 49-52, 2001."None>Sevilla et al. (2001)</a> with axonal Charcot-Marie-Tooth neuropathy and vocal cord paresis (<a href="/entry/607706">607706</a>), <a href="#8" class="mim-tip-reference" title="Cuesta, A., Pedrola, L., Sevilla, T., Garcia-Planells, J., Chumillas, M. J., Mayordomo, F., LeGuern, E., Marin, I., Vilchez, J. J., Palau, F. <strong>The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease.</strong> Nature Genet. 30: 22-24, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11743580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11743580</a>] [<a href="https://doi.org/10.1038/ng798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11743580">Cuesta et al. (2002)</a> identified 3 distinct mutations in the GDAP1 gene (S194X; Q163X, <a href="#0004">606598.0004</a>; 863insA, <a href="#0005">606598.0005</a>). All mutations occurred in the homozygous or compound heterozygous state, consistent with autosomal recessive inheritance. Thus, mutations in GDAP1 can be associated with both axonal and demyelinating phenotypes, as reported for the myelin protein zero gene (MPZ; <a href="/entry/159440">159440</a>) (<a href="#13" class="mim-tip-reference" title="Lewis, R. A., Sumner, A. J., Shy, M. E. <strong>Electrophysiological features of inherited demyelinating neuropathies: a reappraisal in the era of molecular diagnosis.</strong> Muscle Nerve 23: 1472-1487, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11003782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11003782</a>] [<a href="https://doi.org/10.1002/1097-4598(200010)23:10<1472::aid-mus3>3.0.co;2-#" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11003782">Lewis et al., 2000</a>; <a href="#21" class="mim-tip-reference" title="Vance, J. M. <strong>The many faces of Charcot-Marie-Tooth disease.</strong> Arch. Neurol. 57: 638-640, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10815126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10815126</a>] [<a href="https://doi.org/10.1001/archneur.57.5.638" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10815126">Vance, 2000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11003782+11743580+10815126" 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="Nelis, E., Erdem, S., Van den Bergh, P. Y. K., Belpaire-Dethiou, M.-C., Ceuterick, C., Van Gerwen, V., Cuesta, A., Pedrola, L., Palau, F., Gabreels-Festen, A. A. W. M., Verellen, C., Tan, E., Demirci, M., Van Broeckhoven, C., De Jonghe, P., Topaloglu, H., Timmerman, V. <strong>Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy.</strong> Neurology 59: 1865-1872, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12499475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12499475</a>] [<a href="https://doi.org/10.1212/01.wnl.0000036272.36047.54" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12499475">Nelis et al. (2002)</a> pointed out that the mutations in GDAP1 causing early-onset, severe autosomal recessive CMT show a range of nerve conduction velocities with some patients falling in the normal or near normal range, suggesting an axonal neuropathy, whereas others have severely slowed nerve conduction velocities compatible with demyelination. The peripheral nerve biopsy findings are equally variable and show mixed or intermediate features of demyelination and axonal degeneration. In 7 families with autosomal recessive CMT compatible with linkage to the CMT4A locus at 8q21.1, <a href="#15" class="mim-tip-reference" title="Nelis, E., Erdem, S., Van den Bergh, P. Y. K., Belpaire-Dethiou, M.-C., Ceuterick, C., Van Gerwen, V., Cuesta, A., Pedrola, L., Palau, F., Gabreels-Festen, A. A. W. M., Verellen, C., Tan, E., Demirci, M., Van Broeckhoven, C., De Jonghe, P., Topaloglu, H., Timmerman, V. <strong>Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy.</strong> Neurology 59: 1865-1872, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12499475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12499475</a>] [<a href="https://doi.org/10.1212/01.wnl.0000036272.36047.54" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12499475">Nelis et al. (2002)</a> observed homozygosity for 3 distinct mutations in GDAP1 (e.g., R282C, <a href="#0006">606598.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12499475" 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 all 4 affected members of a consanguineous Moroccan family with severe axonal CMT (CMT2K; <a href="/entry/607831">607831</a>), <a href="#2" class="mim-tip-reference" title="Birouk, N., Azzedine, H., Dubourg, O., Muriel, M.-P., Benomar, A., Hamadouche, T., Maisonobe, T., Ouazzani, R., Brice, A., Yahyaoui, M., Chkili, T., LeGuern, E. <strong>Phenotypical features of a Moroccan family with autosomal recessive Charcot-Marie-Tooth disease associated with the S194X mutation in the GDAP1 gene.</strong> Arch. Neurol. 60: 598-604, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707075</a>] [<a href="https://doi.org/10.1001/archneur.60.4.598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12707075">Birouk et al. (2003)</a> identified homozygosity for the S194X mutation in the GDAP1 gene that had previously been identified in patients with CMT4A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12707075" 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="Niemann, A., Ruegg, M., La Padula, V., Schenone, A., Suter, U. <strong>Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease.</strong> J. Cell Biol. 170: 1067-1078, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16172208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16172208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16172208[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.200507087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16172208">Niemann et al. (2005)</a> showed that disease-associated GDAP1 truncation mutants (S194X and 863insA) were not targeted to the mitochondria and lost mitochondrial fragmentation activity, confirming that the C terminus is important for mitochondrial localization. Disease-associated GDAP1 missense mutants (R161H and R282C) were targeted to the mitochondria but showed some impairment in the ability to induce fragmentation compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16172208" 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>Heterozygous GDAP1 Mutations</em></strong></p><p>
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In affected members of 2 unrelated Spanish families with autosomal dominant inheritance of axonal CMT (see <a href="/entry/607831">607831</a>), <a href="#6" class="mim-tip-reference" title="Claramunt, R., Pedrola, L., Sevilla, T., Lopez de Munain, A., Berciano, J., Cuesta, A., Sanchez-Navarro, B., Millan, J. M., Saifi, G. M., Lupski, J. R., Vilchez, J. J., Espinos, C., Palau, F. <strong>Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. (Letter)</strong> J. Med. Genet. 42: 358-365, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805163</a>] [<a href="https://doi.org/10.1136/jmg.2004.022178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15805163">Claramunt et al. (2005)</a> identified a heterozygous mutation in the GDAP1 gene (R120W; <a href="#0009">606598.0009</a>). The patients had onset at the end of their second decade and very slow progression of the disorder, which was a milder phenotype than that seen in most patients carrying 2 GDAP1 mutations. <a href="#6" class="mim-tip-reference" title="Claramunt, R., Pedrola, L., Sevilla, T., Lopez de Munain, A., Berciano, J., Cuesta, A., Sanchez-Navarro, B., Millan, J. M., Saifi, G. M., Lupski, J. R., Vilchez, J. J., Espinos, C., Palau, F. <strong>Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. (Letter)</strong> J. Med. Genet. 42: 358-365, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805163</a>] [<a href="https://doi.org/10.1136/jmg.2004.022178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15805163">Claramunt et al. (2005)</a> noted that autosomal dominant inheritance had not previously been reported in CMT patients with GDAP1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15805163" 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="Chung, K. W., Kim, S. M., Sunwoo, I. N., Cho, S. Y., Hwang, S. J., Kim, J., Kang, S. H., Park, K.-D., Choi, K.-G., Choi, I. S., Choi, B.-O. <strong>A novel GDAP1 Q218E mutation in autosomal dominant Charcot-Marie-Tooth disease.</strong> J. Hum. Genet. 53: 360-364, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18231710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18231710</a>] [<a href="https://doi.org/10.1007/s10038-008-0249-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18231710">Chung et al. (2008)</a> identified a heterozygous mutation in the GDAP1 gene (Q218E; <a href="#0012">606598.0012</a>) in a Korean father and daughter with autosomal dominant adult-onset axonal CMT2K (see <a href="/entry/607831">607831</a>). The phenotype was milder than that usually observed in patients with recessive GDAP1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18231710" 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="Crimella, C., Tonelli, A., Airoldi, G., Baschirotto, C., D'Angelo, M. G., Bonato, S., Losito, L., Trabacca, A., Bresolin, N., Bassi, M. T. <strong>The GST domain of GDAP1 is a frequent target of mutations in the dominant form of axonal Charcot Marie Tooth type 2K.</strong> J. Med. Genet. 47: 712-716, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20685671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20685671</a>] [<a href="https://doi.org/10.1136/jmg.2010.077909" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20685671">Crimella et al. (2010)</a> identified 3 different heterozygous mutations in the GDAP1 gene (see, e.g., R226S, <a href="#0015">606598.0015</a>) in 3 (27%) of 11 Italian probands with dominant inheritance of axonal CMT2K. Two of the mutations occurred in the GST domain, and 1 was a truncating mutation resulting in the elimination of the GST domain, suggesting that the GST domain is a frequent target of mutations for the dominant form of CMT2K. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20685671" 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="Zimon, M., Baets, J., Fabrizi, G. M., Jaakkola, E., Kabzinska, D., Pilch, J., Schindler, A. B., Cornblath, D. R., Fischbeck, K. H., Auer-Grumbach, M., Guelly, C., Huber, N., De Vriendt, E., Timmerman, V., Suter, U., Hausmanowa-Petrusewicz, I., Niemann, A., Kochanski, A., De Jonghe, P., Jordanova, A. <strong>Dominant GDAP1 mutations cause predominantly mild CMT phenotypes.</strong> Neurology 77: 540-548, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21753178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21753178</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21753178[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/10.1212/WNL.0b013e318228fc70" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21753178">Zimon et al. (2011)</a> reported 8 unrelated families with autosomal dominant CMT due to 4 different heterozygous mutations in the GDAP1 gene (<a href="#0009">606598.0009</a>; <a href="#0017">606598.0017</a>-<a href="#0019">606598.0019</a>). The R120W was found in 3 unrelated families of Italian, Austrian, and Ashkenazi Jewish descent, respectively, and haplotype analysis indicated a founder effect. The phenotype varied considerably, even within a family, and some mutation carriers were asymptomatic, consistent with incomplete penetrance. The age at onset ranged from childhood to adulthood, and the most common initial symptom was walking difficulties due to distal muscle weakness and atrophy. The disorder was slowly progressive, but most patients remained ambulatory. A few patients also developed proximal weakness. The majority of patients had an axonal pattern on electrophysiologic studies, but 2 unrelated patients with a more severe phenotype had an intermediate pattern between axonal and demyelinating. <a href="#23" class="mim-tip-reference" title="Zimon, M., Baets, J., Fabrizi, G. M., Jaakkola, E., Kabzinska, D., Pilch, J., Schindler, A. B., Cornblath, D. R., Fischbeck, K. H., Auer-Grumbach, M., Guelly, C., Huber, N., De Vriendt, E., Timmerman, V., Suter, U., Hausmanowa-Petrusewicz, I., Niemann, A., Kochanski, A., De Jonghe, P., Jordanova, A. <strong>Dominant GDAP1 mutations cause predominantly mild CMT phenotypes.</strong> Neurology 77: 540-548, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21753178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21753178</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21753178[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/10.1212/WNL.0b013e318228fc70" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21753178">Zimon et al. (2011)</a> noted that the phenotype in heterozygous GDAP1 mutation carriers was generally milder than that in patients with 2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21753178" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=606598[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, AUTOSOMAL RECESSIVE, TYPE 4A</strong>
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<div class="mim-changed mim-change"><p>In 2 families with demyelinating Charcot-Marie-Tooth disease type 4A (CMT4A; <a href="/entry/214400">214400</a>), <a href="#1" class="mim-tip-reference" title="Baxter, R. V., Ben Othmane, K., Rochelle, J. M., Stajich, J. E., Hulette, C., Dew-Knight, S., Hentati, F., Ben Hamida, M., Bel, S., Stenger, J. E., Gilbert, J. R., Pericak-Vance, M. A., Vance, J. M. <strong>Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21.</strong> Nature Genet. 30: 21-22, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11743579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11743579</a>] [<a href="https://doi.org/10.1038/ng796" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11743579">Baxter et al. (2002)</a> found that affected individuals were homozygous for a c.92G-A transition in exon 1 of the GDAP1 gene that converted tryptophan-31 to a stop codon (W31X) and was predicted to result in a truncated protein. Affected individuals of the 2 families shared a haplotype surrounding the GDAP1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11743579" 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></div>
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<strong>.0002 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, AUTOSOMAL RECESSIVE, TYPE 4A</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> rs104894075 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894075;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/rs104894075?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=rs104894075" 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=rs104894075" 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=RCV000004410 OR RCV000004411 OR RCV000023562 OR RCV000760312 OR RCV002496253" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004410, RCV000004411, RCV000023562, RCV000760312, RCV002496253" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004410...</a>
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<p><strong><em>Charcot-Marie-Tooth Disease, Demyelinating, Type 4A</em></strong></p><p>
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In a Tunisian family with demyelinating Charcot-Marie-Tooth disease type 4A (CMT4A; <a href="/entry/214400">214400</a>), <a href="#1" class="mim-tip-reference" title="Baxter, R. V., Ben Othmane, K., Rochelle, J. M., Stajich, J. E., Hulette, C., Dew-Knight, S., Hentati, F., Ben Hamida, M., Bel, S., Stenger, J. E., Gilbert, J. R., Pericak-Vance, M. A., Vance, J. M. <strong>Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21.</strong> Nature Genet. 30: 21-22, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11743579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11743579</a>] [<a href="https://doi.org/10.1038/ng796" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11743579">Baxter et al. (2002)</a> found that affected individuals were homozygous for a nonsense mutation in exon 5 of the GDAP1 gene, ser194 to stop (S194X), which was predicted to result in a truncated protein. This amino acid substitution was the result of a C-to-G transversion at nucleotide 581 (C581G). This family did not share any haplotype over the entire CMT4 region with any other Tunisian family with this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11743579" 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 consanguineous family, <a href="#15" class="mim-tip-reference" title="Nelis, E., Erdem, S., Van den Bergh, P. Y. K., Belpaire-Dethiou, M.-C., Ceuterick, C., Van Gerwen, V., Cuesta, A., Pedrola, L., Palau, F., Gabreels-Festen, A. A. W. M., Verellen, C., Tan, E., Demirci, M., Van Broeckhoven, C., De Jonghe, P., Topaloglu, H., Timmerman, V. <strong>Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy.</strong> Neurology 59: 1865-1872, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12499475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12499475</a>] [<a href="https://doi.org/10.1212/01.wnl.0000036272.36047.54" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12499475">Nelis et al. (2002)</a> observed homozygosity for this mutation in 2 sisters with autosomal recessive CMT4A. They had onset at ages 2 months and 1 year with foot deformity and hammertoes as the initial symptoms, respectively. At least 1 of them had muscle weakness in both the lower limbs and upper limbs as well as sensory loss and absence of reflexes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12499475" 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 with Vocal Cord Paresis</em></strong></p><p>
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<a href="#8" class="mim-tip-reference" title="Cuesta, A., Pedrola, L., Sevilla, T., Garcia-Planells, J., Chumillas, M. J., Mayordomo, F., LeGuern, E., Marin, I., Vilchez, J. J., Palau, F. <strong>The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease.</strong> Nature Genet. 30: 22-24, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11743580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11743580</a>] [<a href="https://doi.org/10.1038/ng798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11743580">Cuesta et al. (2002)</a> found this mutation in compound heterozygosity with Q163X (<a href="#0004">606598.0004</a>) in a small Spanish family with an axonal CMT phenotype associated with hoarse voice and vocal cord paresis (<a href="/entry/607706">607706</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11743580" 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, Axonal, Type 2K</em></strong></p><p>
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In all 4 affected members of a consanguineous Moroccan family with severe axonal CMT (CMT2K; <a href="/entry/607831">607831</a>), <a href="#2" class="mim-tip-reference" title="Birouk, N., Azzedine, H., Dubourg, O., Muriel, M.-P., Benomar, A., Hamadouche, T., Maisonobe, T., Ouazzani, R., Brice, A., Yahyaoui, M., Chkili, T., LeGuern, E. <strong>Phenotypical features of a Moroccan family with autosomal recessive Charcot-Marie-Tooth disease associated with the S194X mutation in the GDAP1 gene.</strong> Arch. Neurol. 60: 598-604, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707075</a>] [<a href="https://doi.org/10.1001/archneur.60.4.598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12707075">Birouk et al. (2003)</a> identified homozygosity for the S194X mutation in the GDAP1 gene. Vocal cord paresis was not present. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12707075" 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, DEMYELINATING, AUTOSOMAL RECESSIVE, TYPE 4A</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> rs104894076 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894076;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/rs104894076?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=rs104894076" 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=rs104894076" 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=RCV000004412 OR RCV001200307" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004412, RCV001200307" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004412...</a>
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<div class="mim-changed mim-change"><p>In a Tunisian family with demyelinating Charcot-Marie-Tooth disease type 4A (CMT4A; <a href="/entry/214400">214400</a>), <a href="#1" class="mim-tip-reference" title="Baxter, R. V., Ben Othmane, K., Rochelle, J. M., Stajich, J. E., Hulette, C., Dew-Knight, S., Hentati, F., Ben Hamida, M., Bel, S., Stenger, J. E., Gilbert, J. R., Pericak-Vance, M. A., Vance, J. M. <strong>Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21.</strong> Nature Genet. 30: 21-22, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11743579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11743579</a>] [<a href="https://doi.org/10.1038/ng796" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11743579">Baxter et al. (2002)</a> found that affected members were homozygous for a c.482G-A transition in exon 3 of the GDAP1 gene, resulting in an arg161-to-his (R161H) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11743579" 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></div>
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<strong>.0004 NEUROPATHY, AXONAL, WITH VOCAL CORD PARESIS, 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> rs104894077 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894077;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/rs104894077?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=rs104894077" 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=rs104894077" 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=RCV000004413 OR RCV000031963 OR RCV000204463 OR RCV000236485 OR RCV000763605 OR RCV000857207 OR RCV005055503" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004413, RCV000031963, RCV000204463, RCV000236485, RCV000763605, RCV000857207, RCV005055503" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004413...</a>
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<p>In a large inbred Spanish family with autosomal recessive distal axonal neuropathy with hoarseness and vocal cord paresis (<a href="/entry/607706">607706</a>), <a href="#8" class="mim-tip-reference" title="Cuesta, A., Pedrola, L., Sevilla, T., Garcia-Planells, J., Chumillas, M. J., Mayordomo, F., LeGuern, E., Marin, I., Vilchez, J. J., Palau, F. <strong>The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease.</strong> Nature Genet. 30: 22-24, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11743580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11743580</a>] [<a href="https://doi.org/10.1038/ng798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11743580">Cuesta et al. (2002)</a> found that affected members were homoallelic for a gln163-to-stop (Q163X) mutation in the GDAP1 gene, caused by a C-to-T transition at nucleotide 487. In another smaller family, affected members were compound heterozygotes for the Q163X and S194X (<a href="#0002">606598.0002</a>) mutations in the GDAP1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11743580" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Boerkoel, C. F., Takashima, H., Nakagawa, M., Izumo, S., Armstrong, D., Butler, I., Mancias, P., Papasozomenos, S. C. H., Stern, L. Z., Lupski, J. R. <strong>CMT4A: identification of a Hispanic GDAP1 founder mutation.</strong> Ann. Neurol. 53: 400-405, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12601710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12601710</a>] [<a href="https://doi.org/10.1002/ana.10505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12601710">Boerkoel et al. (2003)</a> identified homozygosity for the Q163X mutation in 5 patients from 3 unrelated Hispanic families with an early onset form of autosomal recessive CMT. Based on the finding of a common pathogenic haplotype among all patients, the authors suggested that the Q163X mutation is a founder mutation that may have arisen in Spain. Clinical features of these patients included onset at about the first year of life, with severe distal muscle weakness leading to disability in the second decade of life. One patient had vocal cord weakness. Nerve conduction velocities in 2 patients were consistent with axonal CMT. Histopathologic changes showed both demyelination and axonal loss, as well as onion bulb formations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12601710" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Claramunt, R., Pedrola, L., Sevilla, T., Lopez de Munain, A., Berciano, J., Cuesta, A., Sanchez-Navarro, B., Millan, J. M., Saifi, G. M., Lupski, J. R., Vilchez, J. J., Espinos, C., Palau, F. <strong>Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. (Letter)</strong> J. Med. Genet. 42: 358-365, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805163</a>] [<a href="https://doi.org/10.1136/jmg.2004.022178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15805163">Claramunt et al. (2005)</a> identified homozygosity for the Q163X mutation in affected probands from 4 unrelated families with axonal neuropathy and vocal cord paresis. All patients were of Spanish ancestry. Haplotype analysis indicated a founder effect originating in the Iberian peninsula approximately 33,000 years ago. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15805163" 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 NEUROPATHY, AXONAL, WITH VOCAL CORD PARESIS, 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">rs1586807410 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1586807410;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=rs1586807410" 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=rs1586807410" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<div class="mim-changed mim-change"><p>In a small family of Spanish ancestry, <a href="#8" class="mim-tip-reference" title="Cuesta, A., Pedrola, L., Sevilla, T., Garcia-Planells, J., Chumillas, M. J., Mayordomo, F., LeGuern, E., Marin, I., Vilchez, J. J., Palau, F. <strong>The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease.</strong> Nature Genet. 30: 22-24, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11743580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11743580</a>] [<a href="https://doi.org/10.1038/ng798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11743580">Cuesta et al. (2002)</a> found that the index member affected by distal axonal neuropathy associated with hoarseness and vocal cord paresis (<a href="/entry/607706">607706</a>) was heteroallelic for a 1-bp insertion, c.863insA, in exon 6, leading to a frameshift mutation that generated 2 abnormal amino acids after threonine-288 and terminated the protein at codon 290 (T288fsX290). The 863insA mutation was found in compound heterozygous state with the Q163X mutation (<a href="#0004">606598.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11743580" 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></div>
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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> rs28937906 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28937906;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/rs28937906?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=rs28937906" 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=rs28937906" 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=RCV000004415 OR RCV000235864 OR RCV001235354 OR RCV002504741" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004415, RCV000235864, RCV001235354, RCV002504741" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004415...</a>
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<div class="mim-changed mim-change"><p>In 2 sisters (CMT-136.3 and CMT-136.4) with a mixed form of axonal and demyelinating autosomal recessive Charcot-Marie-Tooth disease (CMTRIA; <a href="/entry/608340">608340</a>) from a consanguineous Turkish family, <a href="#15" class="mim-tip-reference" title="Nelis, E., Erdem, S., Van den Bergh, P. Y. K., Belpaire-Dethiou, M.-C., Ceuterick, C., Van Gerwen, V., Cuesta, A., Pedrola, L., Palau, F., Gabreels-Festen, A. A. W. M., Verellen, C., Tan, E., Demirci, M., Van Broeckhoven, C., De Jonghe, P., Topaloglu, H., Timmerman, V. <strong>Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy.</strong> Neurology 59: 1865-1872, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12499475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12499475</a>] [<a href="https://doi.org/10.1212/01.wnl.0000036272.36047.54" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12499475">Nelis et al. (2002)</a> identified homozygosity for a c.844C-T change in the GDAP1 gene, resulting in an arg282-to-cys (R282C) substitution. The unaffected parents were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12499475" 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></div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1586803063 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1586803063;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=rs1586803063" 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=rs1586803063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<div class="mim-changed mim-change"><p>In 2 affected members of a consanguineous Turkish family (AC531) with autosomal recessive intermediate Charcot-Marie-Tooth disease (CMTRIA; <a href="/entry/608340">608340</a>), <a href="#18" class="mim-tip-reference" title="Senderek, J., Bergmann, C., Ramaekers, V. T., Nelis, E., Bernert, G., Makowski, A., Zuchner, S., De Jonghe, P., Rudnik-Schoneborn, S., Zerres, K., Schroder, J. M. <strong>Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy.</strong> Brain 126: 642-649, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12566285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12566285</a>] [<a href="https://doi.org/10.1093/brain/awg068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12566285">Senderek et al. (2003)</a> identified homozygosity for a 1-bp insertion (c.349_350insT) in exon 3 of the GDAP1 gene, resulting in a premature stop codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12566285" 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></div>
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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> rs864622501 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864622501;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/rs864622501?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=rs864622501" 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=rs864622501" 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=RCV000204949 OR RCV000789161 OR RCV001795333 OR RCV001839450 OR RCV002288831" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000204949, RCV000789161, RCV001795333, RCV001839450, RCV002288831" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000204949...</a>
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<div class="mim-changed mim-change"><p>In a German girl (family AC49) with autosomal recessive intermediate Charcot-Marie-Tooth disease (CMTRIA; <a href="/entry/608340">608340</a>), <a href="#18" class="mim-tip-reference" title="Senderek, J., Bergmann, C., Ramaekers, V. T., Nelis, E., Bernert, G., Makowski, A., Zuchner, S., De Jonghe, P., Rudnik-Schoneborn, S., Zerres, K., Schroder, J. M. <strong>Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy.</strong> Brain 126: 642-649, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12566285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12566285</a>] [<a href="https://doi.org/10.1093/brain/awg068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12566285">Senderek et al. (2003)</a> identified homozygosity for a splice site mutation in the GDAP1 gene (c.579+1G-A), predicted to result in the skipping of exon 4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12566285" 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></div>
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<strong>.0009 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2K</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> rs104894078 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894078;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/rs104894078?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=rs104894078" 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=rs104894078" 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=RCV000004418 OR RCV000192249 OR RCV000200521 OR RCV000236074 OR RCV001225306 OR RCV001535613 OR RCV002453246" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004418, RCV000192249, RCV000200521, RCV000236074, RCV001225306, RCV001535613, RCV002453246" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004418...</a>
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<div class="mim-changed mim-change"><p>In affected members of 2 unrelated Spanish families with autosomal dominant inheritance of axonal Charcot-Marie-Tooth disease type 2K (CMT2K; <a href="/entry/607831">607831</a>), <a href="#6" class="mim-tip-reference" title="Claramunt, R., Pedrola, L., Sevilla, T., Lopez de Munain, A., Berciano, J., Cuesta, A., Sanchez-Navarro, B., Millan, J. M., Saifi, G. M., Lupski, J. R., Vilchez, J. J., Espinos, C., Palau, F. <strong>Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. (Letter)</strong> J. Med. Genet. 42: 358-365, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805163</a>] [<a href="https://doi.org/10.1136/jmg.2004.022178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15805163">Claramunt et al. (2005)</a> identified a heterozygous c.358C-T transition in the GDAP1 gene, resulting in an arg120-to-trp (R120W) substitution in a conserved region of the protein. The patients had onset at the end of the second decade and very slow progression, which was a milder phenotype than that seen in most patients carrying 2 GDAP1 mutations. <a href="#6" class="mim-tip-reference" title="Claramunt, R., Pedrola, L., Sevilla, T., Lopez de Munain, A., Berciano, J., Cuesta, A., Sanchez-Navarro, B., Millan, J. M., Saifi, G. M., Lupski, J. R., Vilchez, J. J., Espinos, C., Palau, F. <strong>Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. (Letter)</strong> J. Med. Genet. 42: 358-365, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805163</a>] [<a href="https://doi.org/10.1136/jmg.2004.022178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15805163">Claramunt et al. (2005)</a> noted that autosomal dominant inheritance had not previously been reported in CMT patients with GDAP1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15805163" 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></div>
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<p><a href="#23" class="mim-tip-reference" title="Zimon, M., Baets, J., Fabrizi, G. M., Jaakkola, E., Kabzinska, D., Pilch, J., Schindler, A. B., Cornblath, D. R., Fischbeck, K. H., Auer-Grumbach, M., Guelly, C., Huber, N., De Vriendt, E., Timmerman, V., Suter, U., Hausmanowa-Petrusewicz, I., Niemann, A., Kochanski, A., De Jonghe, P., Jordanova, A. <strong>Dominant GDAP1 mutations cause predominantly mild CMT phenotypes.</strong> Neurology 77: 540-548, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21753178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21753178</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21753178[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/10.1212/WNL.0b013e318228fc70" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21753178">Zimon et al. (2011)</a> identified a heterozygous R120W substitution in affected members of 3 unrelated families with dominant inheritance of axonal CMT. The families were of Italian, Austrian, and Ashkenazi Jewish descent, respectively. Haplotype analysis indicated a common origin of the mutation, consistent with a founder effect. Expression of the R120W dominant mutation in HeLa cells resulted in impaired mitochondrial fusion, supporting its pathogenicity. The phenotype was considerably variable: age at onset ranged from childhood to adulthood. Walking difficulties were the most common initial symptom and the disorder was slowly progressive, but patients remained ambulatory with mainly distal muscle weakness and atrophy. Two patients also developed proximal weakness. One mutation carrier was asymptomatic, indicating incomplete penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21753178" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>For a discussion of a possible modifier effect on the GDPA1 R120W mutation by a R213P variant in the JPH1 gene, see <a href="/entry/605266#0001">605266.0001</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">rs104894079 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894079;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=rs104894079" 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=rs104894079" 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=RCV000004419 OR RCV000798174 OR RCV001533514" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004419, RCV000798174, RCV001533514" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004419...</a>
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<div class="mim-changed mim-change"><p>In a sporadic case of severe Charcot-Marie-Tooth disease type 2K (CMT2K; see <a href="/entry/607831">607831</a>), <a href="#6" class="mim-tip-reference" title="Claramunt, R., Pedrola, L., Sevilla, T., Lopez de Munain, A., Berciano, J., Cuesta, A., Sanchez-Navarro, B., Millan, J. M., Saifi, G. M., Lupski, J. R., Vilchez, J. J., Espinos, C., Palau, F. <strong>Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. (Letter)</strong> J. Med. Genet. 42: 358-365, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805163</a>] [<a href="https://doi.org/10.1136/jmg.2004.022178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15805163">Claramunt et al. (2005)</a> identified a de novo heterozygous c.469A-C transversion in the GDAP1 gene, resulting in a thr157-to-pro (T157P) substitution. The patient had early onset of symptoms within the first year of life, moderately reduced distal strength in the lower limbs, absent tendon reflexes, and optic atrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15805163" 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></div>
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<strong>.0011 CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE A</strong>
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CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL RECESSIVE, TYPE 2K, 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"><span class="text-primary">●</span> rs104894080 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894080;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/rs104894080?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=rs104894080" 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=rs104894080" 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=RCV000004420 OR RCV000033147 OR RCV000034153 OR RCV000414821 OR RCV000439841 OR RCV000779562 OR RCV000789780 OR RCV002362562 OR RCV002496254" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004420, RCV000033147, RCV000034153, RCV000414821, RCV000439841, RCV000779562, RCV000789780, RCV002362562, RCV002496254" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004420...</a>
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<div class="mim-changed mim-change"><p>In a 39-year-old woman with recessive intermediate Charcot-Marie-Tooth disease (CMTRIA; <a href="/entry/608340">608340</a>), <a href="#10" class="mim-tip-reference" title="Kabzinska, D., Drac, H., Rowinska-Marcinska, K., Fidzianska, A., Kochanski, A., Hausmanowa-Petrusewicz, I. <strong>Early onset Charcot-Marie-Tooth disease caused by a homozygous leu239phe mutation in the GDAP1 gene.</strong> Acta Myol. 25: 34-37, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17039978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17039978</a>]" pmid="17039978">Kabzinska et al. (2006)</a> identified a homozygous c.715C-T transition in exon 6 of the GDAP1 gene, resulting in a leu239-to-phe (L239F) substitution. The patient had early onset of a motor and sensory neuropathy leading to severe disability in the third decade of life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17039978" 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></div>
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<p><strong><em>Charcot-Marie-Tooth Disease, Type 2K</em></strong>
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<p><a href="#12" class="mim-tip-reference" title="Kabzinska, D., Strugalska-Cynowska, H., Kostera-Pruszczyk, A., Ryniewicz, B., Posmyk, R., Midro, A., Seeman, P., Barankova, L., Zimon, M., Baets, J., Timmerman, V., Guergueltcheva, V., Tournev, I., Sarafov, S., De Jonghe, P., Jordanova, A., Hausmanowa-Petrusewicz, I., Kochanski, A. <strong>L239F founder mutation in GDAP1 is associated with a mild Charcot-Marie-Tooth type 4C4 (CMT4C4) phenotype.</strong> Neurogenetics 11: 357-366, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20232219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20232219</a>] [<a href="https://doi.org/10.1007/s10048-010-0237-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20232219">Kabzinska et al. (2010)</a> identified the L239F mutation, either in homozygous state or in compound heterozygous state with another pathogenic GDAP1 mutation (see, e.g., R282C; <a href="#0006">606598.0006</a>), in affected individuals from 4 families and in 2 individual patients, all with early-onset autosomal recessive CMT. Five of the families were Polish and 1 was Bulgarian. The age at onset ranged from 2 to 10 years, and all had gait abnormalities due to lower limb weakness and atrophy. Two patients who were homozygous for the L239F mutation became wheelchair-bound as young adults. Electrophysiologic studies showed that most patients had normal motor and sensory nerve conduction velocities, whereas a few had reduced responses. The diagnosis was autosomal recessive sensorimotor axonal neuropathy (CMT2K; <a href="/entry/607831">607831</a>). Haplotype analysis indicated a founder effect for the L239F mutation, indicating that it is prevalent in the Central and Eastern European populations. <a href="#12" class="mim-tip-reference" title="Kabzinska, D., Strugalska-Cynowska, H., Kostera-Pruszczyk, A., Ryniewicz, B., Posmyk, R., Midro, A., Seeman, P., Barankova, L., Zimon, M., Baets, J., Timmerman, V., Guergueltcheva, V., Tournev, I., Sarafov, S., De Jonghe, P., Jordanova, A., Hausmanowa-Petrusewicz, I., Kochanski, A. <strong>L239F founder mutation in GDAP1 is associated with a mild Charcot-Marie-Tooth type 4C4 (CMT4C4) phenotype.</strong> Neurogenetics 11: 357-366, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20232219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20232219</a>] [<a href="https://doi.org/10.1007/s10048-010-0237-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20232219">Kabzinska et al. (2010)</a> observed that the phenotype resulting from this missense mutation was slightly milder than that associated with GDAP1 nonsense mutations (e.g., S194X; <a href="#0002">606598.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20232219" 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>.0012 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2K</strong>
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GDAP1, GLN218GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908113 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908113;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=rs121908113" 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=rs121908113" 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=RCV000004421 OR RCV003447065" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004421, RCV003447065" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004421...</a>
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<div class="mim-changed mim-change"><p>In a Korean father and daughter with late-onset autosomal dominant axonal Charcot-Marie-Tooth disease type 2K (CMT2K; see <a href="/entry/607831">607831</a>), <a href="#5" class="mim-tip-reference" title="Chung, K. W., Kim, S. M., Sunwoo, I. N., Cho, S. Y., Hwang, S. J., Kim, J., Kang, S. H., Park, K.-D., Choi, K.-G., Choi, I. S., Choi, B.-O. <strong>A novel GDAP1 Q218E mutation in autosomal dominant Charcot-Marie-Tooth disease.</strong> J. Hum. Genet. 53: 360-364, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18231710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18231710</a>] [<a href="https://doi.org/10.1007/s10038-008-0249-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18231710">Chung et al. (2008)</a> identified a heterozygous c.652C-G transversion in the GDAP1 gene, resulting in a gln218-to-glu (Q218E) substitution in a highly conserved region of the glutathione S-transferase core region of the protein. The mutation was not identified in 374 control chromosomes. The patients had onset of gait difficulties at age 25 and 16 years, respectively. Other features included hand muscle atrophy, decreased distal sensation in the upper and lower limbs, and normal or mildly reduced nerve conduction velocities. Sural nerve biopsy findings in the father were consistent with a primarily axonal process, but there were also signs of demyelination. The phenotype in this family was much milder than that observed in patients with recessive GDAP1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18231710" 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></div>
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<strong>.0013 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL RECESSIVE, TYPE 2K</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> rs121908114 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908114;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/rs121908114?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=rs121908114" 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=rs121908114" 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=RCV000004422 OR RCV000214299 OR RCV000703370 OR RCV000857208 OR RCV002362563 OR RCV005041980" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004422, RCV000214299, RCV000703370, RCV000857208, RCV002362563, RCV005041980" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004422...</a>
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<div class="mim-changed mim-change"><p>In 3 sibs from a consanguineous Amish family with autosomal recessive axonal Charcot-Marie-Tooth disease type 2K (CMT2K; <a href="/entry/607831">607831</a>), <a href="#22" class="mim-tip-reference" title="Xin, B., Puffenberger, E., Nye, L., Wiznitzer, M., Wang, H. <strong>A novel mutation in the GDAP1 gene is associated with autosomal recessive Charcot-Marie-Tooth disease in an Amish family.</strong> Clin. Genet. 74: 274-278, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18492089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18492089</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.01018.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18492089">Xin et al. (2008)</a> identified a homozygous c.692C-T transition in exon 5 of the GDAP1 gene, resulting in a pro231-to-leu (P231L) substitution. The patients had childhood onset of distal lower muscle weakness and borderline nerve conduction velocity measurements, consistent with an axonal neuropathy. The disorder was gradually progressive with worsening of the lower limb symptoms, but the patients were still able to do some daily activities in their twenties. There was no vocal cord or hand muscle involvement. The variant was not seen in 100 control chromosomes from a Lancaster County Amish settlement, but was observed in heterozygosity in 7 (14%) of 50 control individuals from a Geauga County Amish settlement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18492089" 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></div>
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<strong>.0014 CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL DOMINANT, TYPE 2K</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> rs121908115 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908115;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/rs121908115?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=rs121908115" 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=rs121908115" 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=RCV000004423 OR RCV003447066" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004423, RCV003447066" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004423...</a>
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<div class="mim-changed mim-change"><p>In 4 affected members of a French family with autosomal dominant Charcot-Marie-Tooth disease type 2K (CMT2K; see <a href="/entry/607831">607831</a>), <a href="#4" class="mim-tip-reference" title="Cassereau, J., Chevrollier, A., Gueguen, N., Malinge, M.-C., Letournel, F., Nicolas, G., Richard, L., Ferre, M., Verny, C., Dubas, F., Procaccio, V., Amati-Bonneau, P., Bonneau, D., Reynier, P. <strong>Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K).</strong> Neurogenetics 10: 145-150, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19089472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19089472</a>] [<a href="https://doi.org/10.1007/s10048-008-0166-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19089472">Cassereau et al. (2009)</a> identified a heterozygous c.719G-A transition in the GDAP1 gene, resulting in a cys240-to-tyr (C240Y) substitution in a conserved residue of the putative GST core region. Mitochondrial respiratory chain complex I activity in patient fibroblasts was 50% lower than controls, but the overall efficiency of ATP production was not affected, indicating compensatory mechanisms. Electron microscopy showed that the tubular mitochondria were 33% larger in diameter and that the mitochondrial mass was 20% greater compared to controls. <a href="#4" class="mim-tip-reference" title="Cassereau, J., Chevrollier, A., Gueguen, N., Malinge, M.-C., Letournel, F., Nicolas, G., Richard, L., Ferre, M., Verny, C., Dubas, F., Procaccio, V., Amati-Bonneau, P., Bonneau, D., Reynier, P. <strong>Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K).</strong> Neurogenetics 10: 145-150, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19089472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19089472</a>] [<a href="https://doi.org/10.1007/s10048-008-0166-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19089472">Cassereau et al. (2009)</a> concluded that, in addition to the regulatory role GDAP1 plays in mitochondrial network dynamics, it may also be involved in energy production and in the control of mitochondrial volume. The authors postulated a dominant-negative effect of the C240Y mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19089472" 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></div>
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<strong>.0015 CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL DOMINANT, TYPE 2K</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">rs267606842 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606842;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=rs267606842" 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=rs267606842" 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=RCV000004424 OR RCV003447067" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004424, RCV003447067" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004424...</a>
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<div class="mim-changed mim-change"><p>In an Italian mother and daughter child with autosomal dominant Charcot-Marie-Tooth disease type 2K (CMT2K; see <a href="/entry/607831">607831</a>), <a href="#7" class="mim-tip-reference" title="Crimella, C., Tonelli, A., Airoldi, G., Baschirotto, C., D'Angelo, M. G., Bonato, S., Losito, L., Trabacca, A., Bresolin, N., Bassi, M. T. <strong>The GST domain of GDAP1 is a frequent target of mutations in the dominant form of axonal Charcot Marie Tooth type 2K.</strong> J. Med. Genet. 47: 712-716, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20685671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20685671</a>] [<a href="https://doi.org/10.1136/jmg.2010.077909" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20685671">Crimella et al. (2010)</a> identified a heterozygous c.678A-T transversion in exon 5 of the GDAP1 gene, resulting in an arg226-to-ser (R226S) substitution in a highly conserved region in the GST domain. The 25-year-old daughter presented with lower limb involvement at age 8 years and retained independent ambulation. The 49-year-old mother had EMG findings of axonal CMT at age 35 years but showed no clinical signs of the disorder. She developed mild lower limb involvement in her late forties. The mutation was not found in 500 controls. The family illustrated significant intrafamilial variability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20685671" 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></div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397515432 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515432;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=rs397515432" 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=rs397515432" 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=RCV000033148 OR RCV001055971 OR RCV003152669 OR RCV003447102 OR RCV005049398" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033148, RCV001055971, RCV003152669, RCV003447102, RCV005049398" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033148...</a>
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<div class="mim-changed mim-change"><p>In 2 sisters from a small village in northeast Poland with a mixed form of axonal and demyelinating autosomal recessive Charcot-Marie-Tooth disease (CMTRIA; <a href="/entry/608340">608340</a>), <a href="#11" class="mim-tip-reference" title="Kabzinska, D., Niemann, A., Drac, H., Huber, N., Potulska-Chromik, A., Hausmanowa-Petrusewicz, I., Suter, U., Kochanski, A. <strong>A new missense GDAP1 mutation disturbing targeting to the mitochondrial membrane causes a severe from of AR-CMT2C disease.</strong> Neurogenetics 12: 145-153, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21365284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21365284</a>] [<a href="https://doi.org/10.1007/s10048-011-0276-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21365284">Kabzinska et al. (2011)</a> identified a homozygous c.980G-A transition in the GDAP1 gene, resulting in a gly327-to-asp (G327D) substitution in the transmembrane domain, which is important for targeting to the mitochondrial outer membrane. In vitro functional expression studies showed that the mutation interfered with mitochondrial targeting and insertion into the mitochondrial membrane. Cells with overexpression of GDAP1 had a predominantly fragmented mitochondrial morphology, consistent with its role as a mitochondrial fission factor. Cells expressing the G327D mutant protein showed no change in mitochondrial morphology compared to controls, indicating a complete loss of normal fission activity. <a href="#11" class="mim-tip-reference" title="Kabzinska, D., Niemann, A., Drac, H., Huber, N., Potulska-Chromik, A., Hausmanowa-Petrusewicz, I., Suter, U., Kochanski, A. <strong>A new missense GDAP1 mutation disturbing targeting to the mitochondrial membrane causes a severe from of AR-CMT2C disease.</strong> Neurogenetics 12: 145-153, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21365284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21365284</a>] [<a href="https://doi.org/10.1007/s10048-011-0276-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21365284">Kabzinska et al. (2011)</a> commented that this missense GDAP1 mutation resulted in a severe phenotype usually associated with nonsense mutations, and that the complete loss of fission activity on a cellular level correlates with a severe phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21365284" 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></div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397515441 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515441;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=rs397515441" 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=rs397515441" 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=RCV000043548 OR RCV002513634" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043548, RCV002513634" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043548...</a>
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<p>In affected members of 2 distantly related Polish families with autosomal dominant Charcot-Marie-Tooth disease type 2K (CMT2K; <a href="/entry/607831">607831</a>), <a href="#23" class="mim-tip-reference" title="Zimon, M., Baets, J., Fabrizi, G. M., Jaakkola, E., Kabzinska, D., Pilch, J., Schindler, A. B., Cornblath, D. R., Fischbeck, K. H., Auer-Grumbach, M., Guelly, C., Huber, N., De Vriendt, E., Timmerman, V., Suter, U., Hausmanowa-Petrusewicz, I., Niemann, A., Kochanski, A., De Jonghe, P., Jordanova, A. <strong>Dominant GDAP1 mutations cause predominantly mild CMT phenotypes.</strong> Neurology 77: 540-548, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21753178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21753178</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21753178[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/10.1212/WNL.0b013e318228fc70" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21753178">Zimon et al. (2011)</a> identified a heterozygous c.467C-G transversion in the GDAP1 gene, resulting in an ala156-to-gly (A156G) substitution at a highly conserved residue. One unaffected family member carried the mutation, consistent with incomplete penetrance. The mutation was not found in 280 control individuals. Expression of this dominant mutation in HeLa cells resulted in impaired mitochondrial fusion, caused mitochondrial fragmentation, and increased cell sensitivity to apoptosis. The patients had onset in the first or second decades of walking difficulties due to distal muscle weakness and atrophy. The disorder was slowly progressive, and all patients remained ambulatory. Nerve conduction velocities showed an axonal pattern. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21753178" 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, AUTOSOMAL DOMINANT, TYPE 2K</strong>
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GDAP1, HIS123ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397515442 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515442;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=rs397515442" 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=rs397515442" 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=RCV000043549 OR RCV000254797 OR RCV000696667 OR RCV000857206" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043549, RCV000254797, RCV000696667, RCV000857206" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043549...</a>
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<p>In 3 affected members of a large Finnish family with autosomal dominant Charcot-Marie-Tooth disease type 2K (CMT2K; see <a href="/entry/607831">607831</a>), <a href="#23" class="mim-tip-reference" title="Zimon, M., Baets, J., Fabrizi, G. M., Jaakkola, E., Kabzinska, D., Pilch, J., Schindler, A. B., Cornblath, D. R., Fischbeck, K. H., Auer-Grumbach, M., Guelly, C., Huber, N., De Vriendt, E., Timmerman, V., Suter, U., Hausmanowa-Petrusewicz, I., Niemann, A., Kochanski, A., De Jonghe, P., Jordanova, A. <strong>Dominant GDAP1 mutations cause predominantly mild CMT phenotypes.</strong> Neurology 77: 540-548, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21753178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21753178</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21753178[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/10.1212/WNL.0b013e318228fc70" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21753178">Zimon et al. (2011)</a> identified a heterozygous c.358A-G transition in the GDAP1 gene, resulting in a his123-to-arg (H123R) substitution. (The nucleotide numbering was based on a revised transcript.) Four older asymptomatic family members also carried the mutation, indicating incomplete penetrance. The mutation was not found in 280 control individuals. The phenotype was variable, with onset of difficulty walking due to distal muscle weakness and atrophy between 3 and 32 years of age. The disorder was slowly progressive, and all patients remained ambulatory. One patient had proximal weakness. Nerve conduction studies showed an axonal pattern. A heterozygous H123R mutation occurred de novo in a patient of Tunisian origin who was more severely affected and showed delayed motor development; that patient had intermediate results on electrophysiologic studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21753178" 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>.0019 CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL DOMINANT, TYPE 2K</strong>
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GDAP1, PRO274LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397515443 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515443;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=rs397515443" 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=rs397515443" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000043550" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043550" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043550</a>
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<span class="mim-text-font">
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<div class="mim-changed mim-change"><p>In an Italian father and son with autosomal dominant Charcot-Marie-Tooth disease type 2K (CMT2K; see <a href="/entry/607831">607831</a>), <a href="#23" class="mim-tip-reference" title="Zimon, M., Baets, J., Fabrizi, G. M., Jaakkola, E., Kabzinska, D., Pilch, J., Schindler, A. B., Cornblath, D. R., Fischbeck, K. H., Auer-Grumbach, M., Guelly, C., Huber, N., De Vriendt, E., Timmerman, V., Suter, U., Hausmanowa-Petrusewicz, I., Niemann, A., Kochanski, A., De Jonghe, P., Jordanova, A. <strong>Dominant GDAP1 mutations cause predominantly mild CMT phenotypes.</strong> Neurology 77: 540-548, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21753178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21753178</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21753178[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/10.1212/WNL.0b013e318228fc70" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21753178">Zimon et al. (2011)</a> identified a heterozygous c.821C-T transition in the GDAP1 gene, resulting in a pro274-to-leu (P274L) substitution at a highly conserved residue in the C-terminal GST domain. The mutation was not found in 280 control individuals. The father, who had onset of distal muscle weakness and atrophy at age 47 years and became wheelchair-bound at age 61, had an intermediate pattern on nerve conduction studies. The son was clinically asymptomatic, but showed an axonal pattern on nerve conduction studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21753178" 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></div>
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<strong>REFERENCES</strong>
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<a id="Baxter2002" class="mim-anchor"></a>
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Baxter, R. V., Ben Othmane, K., Rochelle, J. M., Stajich, J. E., Hulette, C., Dew-Knight, S., Hentati, F., Ben Hamida, M., Bel, S., Stenger, J. E., Gilbert, J. R., Pericak-Vance, M. A., Vance, J. M.
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<strong>Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21.</strong>
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Nature Genet. 30: 21-22, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11743579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11743579</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11743579" 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/ng796" target="_blank">Full Text</a>]
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Birouk, N., Azzedine, H., Dubourg, O., Muriel, M.-P., Benomar, A., Hamadouche, T., Maisonobe, T., Ouazzani, R., Brice, A., Yahyaoui, M., Chkili, T., LeGuern, E.
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<strong>Phenotypical features of a Moroccan family with autosomal recessive Charcot-Marie-Tooth disease associated with the S194X mutation in the GDAP1 gene.</strong>
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Arch. Neurol. 60: 598-604, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707075</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12707075" 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/archneur.60.4.598" target="_blank">Full Text</a>]
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<a id="Boerkoel2003" class="mim-anchor"></a>
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Boerkoel, C. F., Takashima, H., Nakagawa, M., Izumo, S., Armstrong, D., Butler, I., Mancias, P., Papasozomenos, S. C. H., Stern, L. Z., Lupski, J. R.
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<strong>CMT4A: identification of a Hispanic GDAP1 founder mutation.</strong>
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Ann. Neurol. 53: 400-405, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12601710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12601710</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12601710" 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/10.1002/ana.10505" target="_blank">Full Text</a>]
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Cassereau, J., Chevrollier, A., Gueguen, N., Malinge, M.-C., Letournel, F., Nicolas, G., Richard, L., Ferre, M., Verny, C., Dubas, F., Procaccio, V., Amati-Bonneau, P., Bonneau, D., Reynier, P.
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<strong>Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K).</strong>
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Neurogenetics 10: 145-150, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19089472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19089472</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19089472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10048-008-0166-9" target="_blank">Full Text</a>]
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Chung, K. W., Kim, S. M., Sunwoo, I. N., Cho, S. Y., Hwang, S. J., Kim, J., Kang, S. H., Park, K.-D., Choi, K.-G., Choi, I. S., Choi, B.-O.
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<strong>A novel GDAP1 Q218E mutation in autosomal dominant Charcot-Marie-Tooth disease.</strong>
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J. Hum. Genet. 53: 360-364, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18231710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18231710</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18231710" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10038-008-0249-3" target="_blank">Full Text</a>]
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Claramunt, R., Pedrola, L., Sevilla, T., Lopez de Munain, A., Berciano, J., Cuesta, A., Sanchez-Navarro, B., Millan, J. M., Saifi, G. M., Lupski, J. R., Vilchez, J. J., Espinos, C., Palau, F.
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<strong>Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. (Letter)</strong>
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J. Med. Genet. 42: 358-365, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805163</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15805163" 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.2004.022178" target="_blank">Full Text</a>]
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<strong>The GST domain of GDAP1 is a frequent target of mutations in the dominant form of axonal Charcot Marie Tooth type 2K.</strong>
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[<a href="https://doi.org/10.1136/jmg.2010.077909" target="_blank">Full Text</a>]
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<strong>The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease.</strong>
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[<a href="https://doi.org/10.1038/ng798" target="_blank">Full Text</a>]
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<strong>A new missense GDAP1 mutation disturbing targeting to the mitochondrial membrane causes a severe from of AR-CMT2C disease.</strong>
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[<a href="https://doi.org/10.1007/s10048-011-0276-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10048-010-0237-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/1097-4598(200010)23:10<1472::aid-mus3>3.0.co;2-#" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1046/j.1471-4159.1999.0721781.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000036272.36047.54" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1083/jcb.200507087" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi121" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/awg068" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.bbrc.2006.06.189" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21753178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21753178</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21753178[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=21753178" 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.0b013e318228fc70" target="_blank">Full Text</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 : 10/20/2015
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<span class="mim-text-font">
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Matthew B. Gross - updated : 8/27/2013<br>Cassandra L. Kniffin - updated : 5/16/2013<br>Cassandra L. Kniffin - updated : 2/7/2013<br>Cassandra L. Kniffin - updated : 11/23/2010<br>Cassandra L. Kniffin - updated : 5/14/2009<br>Cassandra L. Kniffin - updated : 4/29/2009<br>Cassandra L. Kniffin - updated : 7/7/2008<br>George E. Tiller - updated : 2/7/2008<br>Cassandra L. Kniffin - updated : 9/18/2006<br>Cassandra L. Kniffin - updated : 5/18/2005<br>Cassandra L. Kniffin - updated : 2/9/2004<br>Cassandra L. Kniffin - updated : 12/12/2003<br>Cassandra L. Kniffin - updated : 5/27/2003<br>Cassandra L. Kniffin - reorganized : 5/9/2003<br>Cassandra L. Kniffin - updated : 5/9/2003<br>Victor A. McKusick - updated : 1/21/2003<br>Victor A. McKusick - updated : 1/8/2002
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse : 1/7/2002
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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alopez : 12/12/2024
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carol : 09/12/2024<br>carol : 04/26/2023<br>carol : 10/18/2016<br>alopez : 12/07/2015<br>ckniffin : 10/20/2015<br>mgross : 8/27/2013<br>carol : 8/27/2013<br>ckniffin : 8/26/2013<br>carol : 5/28/2013<br>ckniffin : 5/16/2013<br>alopez : 2/19/2013<br>ckniffin : 2/7/2013<br>wwang : 11/29/2010<br>ckniffin : 11/23/2010<br>terry : 9/9/2010<br>wwang : 5/29/2009<br>ckniffin : 5/14/2009<br>wwang : 5/12/2009<br>ckniffin : 4/29/2009<br>ckniffin : 1/20/2009<br>wwang : 7/10/2008<br>ckniffin : 7/7/2008<br>wwang : 2/18/2008<br>terry : 2/7/2008<br>wwang : 10/2/2006<br>ckniffin : 9/18/2006<br>terry : 2/3/2006<br>wwang : 6/28/2005<br>wwang : 6/27/2005<br>ckniffin : 5/18/2005<br>ckniffin : 4/20/2004<br>ckniffin : 2/9/2004<br>carol : 12/12/2003<br>ckniffin : 12/12/2003<br>carol : 5/29/2003<br>ckniffin : 5/27/2003<br>carol : 5/9/2003<br>carol : 5/9/2003<br>ckniffin : 5/2/2003<br>ckniffin : 5/1/2003<br>cwells : 1/27/2003<br>tkritzer : 1/21/2003<br>terry : 3/11/2002<br>terry : 3/6/2002<br>alopez : 1/9/2002<br>alopez : 1/9/2002<br>alopez : 1/9/2002<br>terry : 1/8/2002<br>mgross : 1/7/2002
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<span class="mim-font">
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<strong>*</strong> 606598
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<h3>
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<span class="mim-font">
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GANGLIOSIDE-INDUCED DIFFERENTIATION-ASSOCIATED PROTEIN 1; GDAP1
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: GDAP1</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 715796006, 719512003, 725047007;
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<strong>
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<em>
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Cytogenetic location: 8q21.11
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Genomic coordinates <span class="small">(GRCh38)</span> : 8:74,350,403-74,488,872 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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8q21.11
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<span class="mim-font">
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Charcot-Marie-Tooth disease, axonal, type 2K
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</td>
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<td>
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<span class="mim-font">
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607831
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<td>
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<span class="mim-font">
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Autosomal dominant; Autosomal recessive
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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 class="mim-font">
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Charcot-Marie-Tooth disease, axonal, with vocal cord paresis
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</td>
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<td>
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<span class="mim-font">
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607706
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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 class="mim-font">
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Charcot-Marie-Tooth disease, recessive intermediate, A
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</span>
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</td>
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<td>
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<span class="mim-font">
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608340
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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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<td>
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<span class="mim-font">
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Charcot-Marie-Tooth disease, type 4A
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</td>
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<td>
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<span class="mim-font">
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214400
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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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</tbody>
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</table>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>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 GDAP1 gene encodes a protein expressed in the central and peripheral nervous system, particularly in Schwann cells. GDAP1 is an integral membrane protein of the outer mitochondrial membrane (Niemann et al., 2005). </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>Gangliosides, sialic acid-containing glycosphingolipids, are abundant in brain tissue, and GD3 synthase (SIAT8; 601123) plays a key role in their biosynthesis. Using differential display PCR to identify cDNAs induced at different time points by GD3 synthase expression in a mouse neuroblastoma cell line, Liu et al. (1999) obtained cDNAs encoding 10 Gdap proteins, including Gdap1. The deduced 358-amino acid human GDAP1 protein is 94% identical to the mouse protein, with most divergence at the N terminus. Northern blot analysis revealed expression of a 4.1-kb Gdap1 transcript restricted to mouse brain tissue. Immunofluorescence microscopy demonstrated cytoplasmic expression in mouse cells. </p><p>Pedrola et al. (2005) stated that GDAP1 contains 2 N-terminal GST domains and 2 C-terminal transmembrane domains. Real-time PCR of adult rat tissues detected highest expression in spinal cord, dorsal root ganglia, and brain, with low expression in sciatic nerve, and no expression in liver or muscle. GDAP1 localized to the mitochondria in a human neuroblastoma cell line and in COS-7 cells. Western blot analysis of subcellular fractions with anti-GDAP1 antibody detected a 40-kD band corresponding to GDAP1 and an 88-kD band, suggesting that GDAP1 forms a homodimer. The C-terminal transmembrane domains were necessary for correct localization in mitochondria; however, missense mutations did not alter mitochondrial localization. </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>Cuesta et al. (2002) determined that the GDAP1 gene contains 6 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>Xin et al. (2008) noted that the GDAP1 gene maps to chromosome 8q13.1-q21.1. </p><p>Gross (2013) mapped the GDAP1 gene to chromosome 8q21.11 based on an alignment of the GDAP1 sequence (GenBank BC024939) with the genomic sequence (GRCh37).</p>
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</span>
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<div>
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<br />
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</div>
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<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>The GDAP1 gene may be involved in a signal transduction pathway in neuronal development. By Northern blot analysis, Cuesta et al. (2002) showed greatest GDAP1 expression in whole brain and spinal cord. Amplification of human sural nerve and mouse sciatic nerve transcripts suggested that GDAP1 expression does not occur just in neurons but also in Schwann cells. However, GDAP1 expression is higher in central tissues than in peripheral nerves. </p><p>Niemann et al. (2005) demonstrated that Gdap1 was expressed in both Schwann cells and neurons of rat peripheral nerve, as well as in various regions of the central nervous system. Subcellular localization studies showed that Gdap1 is an integral membrane protein of the outer mitochondrial membrane. Overexpression of Gdap1 induced fragmentation of mitochondria without inducing apoptosis, affecting overall mitochondrial activity, or interfering with mitochondrial fusion. The mitochondrial fusion proteins, mitofusin-1 (MFN1; 608506) and -2 (MFN2; 608507) and Drp1 (603850) were able to counterbalance these effects. Gdap1-specific knockdown by RNA interference resulted in a tubular mitochondrial morphology. Niemann et al. (2005) concluded that GDAP1 regulates mitochondrial dynamics that are critical for the proper function of myelinated peripheral nerves. </p><p>Pedrola et al. (2005) found that GST-activity assay detected no activity for soluble GDAP1. Shield et al. (2006) confirmed that the GDAP1 protein does not have glutathione transferase activity, although it appears to be structurally related to other cytosolic glutathione S-transferases (GST). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Homozygous or Compound Heterozygous GDAP1 Mutations</em></strong></p><p>
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In 4 different Tunisian families with Charcot-Marie-Tooth disease type 4A (CMT4A; 214400), an autosomal recessive form of demyelinating peripheral neuropathy mapping to chromosome 8, Baxter et al. (2002) found homozygosity for 2 nonsense mutations and 1 missense mutation in the GDAP1 gene (W31X, 606598.0001; S194X, 606598.0002; R161H, 606598.0003). </p><p>In 3 Spanish families reported by Sevilla et al. (2001) with axonal Charcot-Marie-Tooth neuropathy and vocal cord paresis (607706), Cuesta et al. (2002) identified 3 distinct mutations in the GDAP1 gene (S194X; Q163X, 606598.0004; 863insA, 606598.0005). All mutations occurred in the homozygous or compound heterozygous state, consistent with autosomal recessive inheritance. Thus, mutations in GDAP1 can be associated with both axonal and demyelinating phenotypes, as reported for the myelin protein zero gene (MPZ; 159440) (Lewis et al., 2000; Vance, 2000). </p><p>Nelis et al. (2002) pointed out that the mutations in GDAP1 causing early-onset, severe autosomal recessive CMT show a range of nerve conduction velocities with some patients falling in the normal or near normal range, suggesting an axonal neuropathy, whereas others have severely slowed nerve conduction velocities compatible with demyelination. The peripheral nerve biopsy findings are equally variable and show mixed or intermediate features of demyelination and axonal degeneration. In 7 families with autosomal recessive CMT compatible with linkage to the CMT4A locus at 8q21.1, Nelis et al. (2002) observed homozygosity for 3 distinct mutations in GDAP1 (e.g., R282C, 606598.0006). </p><p>In all 4 affected members of a consanguineous Moroccan family with severe axonal CMT (CMT2K; 607831), Birouk et al. (2003) identified homozygosity for the S194X mutation in the GDAP1 gene that had previously been identified in patients with CMT4A. </p><p>Niemann et al. (2005) showed that disease-associated GDAP1 truncation mutants (S194X and 863insA) were not targeted to the mitochondria and lost mitochondrial fragmentation activity, confirming that the C terminus is important for mitochondrial localization. Disease-associated GDAP1 missense mutants (R161H and R282C) were targeted to the mitochondria but showed some impairment in the ability to induce fragmentation compared to wildtype. </p><p><strong><em>Heterozygous GDAP1 Mutations</em></strong></p><p>
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In affected members of 2 unrelated Spanish families with autosomal dominant inheritance of axonal CMT (see 607831), Claramunt et al. (2005) identified a heterozygous mutation in the GDAP1 gene (R120W; 606598.0009). The patients had onset at the end of their second decade and very slow progression of the disorder, which was a milder phenotype than that seen in most patients carrying 2 GDAP1 mutations. Claramunt et al. (2005) noted that autosomal dominant inheritance had not previously been reported in CMT patients with GDAP1 mutations. </p><p>Chung et al. (2008) identified a heterozygous mutation in the GDAP1 gene (Q218E; 606598.0012) in a Korean father and daughter with autosomal dominant adult-onset axonal CMT2K (see 607831). The phenotype was milder than that usually observed in patients with recessive GDAP1 mutations. </p><p>Crimella et al. (2010) identified 3 different heterozygous mutations in the GDAP1 gene (see, e.g., R226S, 606598.0015) in 3 (27%) of 11 Italian probands with dominant inheritance of axonal CMT2K. Two of the mutations occurred in the GST domain, and 1 was a truncating mutation resulting in the elimination of the GST domain, suggesting that the GST domain is a frequent target of mutations for the dominant form of CMT2K. </p><p>Zimon et al. (2011) reported 8 unrelated families with autosomal dominant CMT due to 4 different heterozygous mutations in the GDAP1 gene (606598.0009; 606598.0017-606598.0019). The R120W was found in 3 unrelated families of Italian, Austrian, and Ashkenazi Jewish descent, respectively, and haplotype analysis indicated a founder effect. The phenotype varied considerably, even within a family, and some mutation carriers were asymptomatic, consistent with incomplete penetrance. The age at onset ranged from childhood to adulthood, and the most common initial symptom was walking difficulties due to distal muscle weakness and atrophy. The disorder was slowly progressive, but most patients remained ambulatory. A few patients also developed proximal weakness. The majority of patients had an axonal pattern on electrophysiologic studies, but 2 unrelated patients with a more severe phenotype had an intermediate pattern between axonal and demyelinating. Zimon et al. (2011) noted that the phenotype in heterozygous GDAP1 mutation carriers was generally milder than that in patients with 2 mutations. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>19 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, AUTOSOMAL RECESSIVE, TYPE 4A</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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GDAP1, TRP31TER
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<br />
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SNP: rs121908112,
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ClinVar: RCV000004409
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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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<div class="mim-changed mim-change"><p>In 2 families with demyelinating Charcot-Marie-Tooth disease type 4A (CMT4A; 214400), Baxter et al. (2002) found that affected individuals were homozygous for a c.92G-A transition in exon 1 of the GDAP1 gene that converted tryptophan-31 to a stop codon (W31X) and was predicted to result in a truncated protein. Affected individuals of the 2 families shared a haplotype surrounding the GDAP1 gene. </p></div>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, AUTOSOMAL RECESSIVE, TYPE 4A</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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CHARCOT-MARIE-TOOTH DISEASE, AXONAL, WITH VOCAL CORD PARESIS, AUTOSOMAL RECESSIVE, INCLUDED<br />
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CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL RECESSIVE, TYPE 2K, INCLUDED
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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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GDAP1, SER194TER
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<br />
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SNP: rs104894075,
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gnomAD: rs104894075,
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ClinVar: RCV000004410, RCV000004411, RCV000023562, RCV000760312, RCV002496253
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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 />
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<p><strong><em>Charcot-Marie-Tooth Disease, Demyelinating, Type 4A</em></strong></p><p>
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In a Tunisian family with demyelinating Charcot-Marie-Tooth disease type 4A (CMT4A; 214400), Baxter et al. (2002) found that affected individuals were homozygous for a nonsense mutation in exon 5 of the GDAP1 gene, ser194 to stop (S194X), which was predicted to result in a truncated protein. This amino acid substitution was the result of a C-to-G transversion at nucleotide 581 (C581G). This family did not share any haplotype over the entire CMT4 region with any other Tunisian family with this disorder. </p><p>In a consanguineous family, Nelis et al. (2002) observed homozygosity for this mutation in 2 sisters with autosomal recessive CMT4A. They had onset at ages 2 months and 1 year with foot deformity and hammertoes as the initial symptoms, respectively. At least 1 of them had muscle weakness in both the lower limbs and upper limbs as well as sensory loss and absence of reflexes. </p><p><strong><em>Charcot-Marie-Tooth Disease with Vocal Cord Paresis</em></strong></p><p>
|
|
Cuesta et al. (2002) found this mutation in compound heterozygosity with Q163X (606598.0004) in a small Spanish family with an axonal CMT phenotype associated with hoarse voice and vocal cord paresis (607706). </p><p><strong><em>Charcot-Marie-Tooth Disease, Axonal, Type 2K</em></strong></p><p>
|
|
In all 4 affected members of a consanguineous Moroccan family with severe axonal CMT (CMT2K; 607831), Birouk et al. (2003) identified homozygosity for the S194X mutation in the GDAP1 gene. Vocal cord paresis was not present. </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>.0003 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, AUTOSOMAL RECESSIVE, TYPE 4A</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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GDAP1, ARG161HIS
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<br />
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SNP: rs104894076,
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gnomAD: rs104894076,
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ClinVar: RCV000004412, RCV001200307
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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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|
<div class="mim-changed mim-change"><p>In a Tunisian family with demyelinating Charcot-Marie-Tooth disease type 4A (CMT4A; 214400), Baxter et al. (2002) found that affected members were homozygous for a c.482G-A transition in exon 3 of the GDAP1 gene, resulting in an arg161-to-his (R161H) substitution. </p></div>
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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>.0004 NEUROPATHY, AXONAL, WITH VOCAL CORD PARESIS, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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|
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GDAP1, GLN163TER
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<br />
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|
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SNP: rs104894077,
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|
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gnomAD: rs104894077,
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|
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ClinVar: RCV000004413, RCV000031963, RCV000204463, RCV000236485, RCV000763605, RCV000857207, RCV005055503
|
|
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|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a large inbred Spanish family with autosomal recessive distal axonal neuropathy with hoarseness and vocal cord paresis (607706), Cuesta et al. (2002) found that affected members were homoallelic for a gln163-to-stop (Q163X) mutation in the GDAP1 gene, caused by a C-to-T transition at nucleotide 487. In another smaller family, affected members were compound heterozygotes for the Q163X and S194X (606598.0002) mutations in the GDAP1 gene. </p><p>Boerkoel et al. (2003) identified homozygosity for the Q163X mutation in 5 patients from 3 unrelated Hispanic families with an early onset form of autosomal recessive CMT. Based on the finding of a common pathogenic haplotype among all patients, the authors suggested that the Q163X mutation is a founder mutation that may have arisen in Spain. Clinical features of these patients included onset at about the first year of life, with severe distal muscle weakness leading to disability in the second decade of life. One patient had vocal cord weakness. Nerve conduction velocities in 2 patients were consistent with axonal CMT. Histopathologic changes showed both demyelination and axonal loss, as well as onion bulb formations. </p><p>Claramunt et al. (2005) identified homozygosity for the Q163X mutation in affected probands from 4 unrelated families with axonal neuropathy and vocal cord paresis. All patients were of Spanish ancestry. Haplotype analysis indicated a founder effect originating in the Iberian peninsula approximately 33,000 years ago. </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>.0005 NEUROPATHY, AXONAL, WITH VOCAL CORD PARESIS, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
GDAP1, 1-BP INS, 863A
|
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|
|
|
|
<br />
|
|
|
|
SNP: rs1586807410,
|
|
|
|
|
|
|
|
ClinVar: RCV000004414
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a small family of Spanish ancestry, Cuesta et al. (2002) found that the index member affected by distal axonal neuropathy associated with hoarseness and vocal cord paresis (607706) was heteroallelic for a 1-bp insertion, c.863insA, in exon 6, leading to a frameshift mutation that generated 2 abnormal amino acids after threonine-288 and terminated the protein at codon 290 (T288fsX290). The 863insA mutation was found in compound heterozygous state with the Q163X mutation (606598.0004). </p></div>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE A</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GDAP1, ARG282CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28937906,
|
|
|
|
|
|
gnomAD: rs28937906,
|
|
|
|
|
|
ClinVar: RCV000004415, RCV000235864, RCV001235354, RCV002504741
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In 2 sisters (CMT-136.3 and CMT-136.4) with a mixed form of axonal and demyelinating autosomal recessive Charcot-Marie-Tooth disease (CMTRIA; 608340) from a consanguineous Turkish family, Nelis et al. (2002) identified homozygosity for a c.844C-T change in the GDAP1 gene, resulting in an arg282-to-cys (R282C) substitution. The unaffected parents were heterozygous for the mutation. </p></div>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE A</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GDAP1, 1-BP INS, 349T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1586803063,
|
|
|
|
|
|
|
|
ClinVar: RCV000004416, RCV000789162, RCV003447194
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In 2 affected members of a consanguineous Turkish family (AC531) with autosomal recessive intermediate Charcot-Marie-Tooth disease (CMTRIA; 608340), Senderek et al. (2003) identified homozygosity for a 1-bp insertion (c.349_350insT) in exon 3 of the GDAP1 gene, resulting in a premature stop codon. </p></div>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE A</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GDAP1, IVS4DS, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs864622501,
|
|
|
|
|
|
gnomAD: rs864622501,
|
|
|
|
|
|
ClinVar: RCV000204949, RCV000789161, RCV001795333, RCV001839450, RCV002288831
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a German girl (family AC49) with autosomal recessive intermediate Charcot-Marie-Tooth disease (CMTRIA; 608340), Senderek et al. (2003) identified homozygosity for a splice site mutation in the GDAP1 gene (c.579+1G-A), predicted to result in the skipping of exon 4. </p></div>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2K</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
GDAP1, ARG120TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894078,
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|
|
|
|
|
gnomAD: rs104894078,
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|
|
|
|
|
ClinVar: RCV000004418, RCV000192249, RCV000200521, RCV000236074, RCV001225306, RCV001535613, RCV002453246
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In affected members of 2 unrelated Spanish families with autosomal dominant inheritance of axonal Charcot-Marie-Tooth disease type 2K (CMT2K; 607831), Claramunt et al. (2005) identified a heterozygous c.358C-T transition in the GDAP1 gene, resulting in an arg120-to-trp (R120W) substitution in a conserved region of the protein. The patients had onset at the end of the second decade and very slow progression, which was a milder phenotype than that seen in most patients carrying 2 GDAP1 mutations. Claramunt et al. (2005) noted that autosomal dominant inheritance had not previously been reported in CMT patients with GDAP1 mutations. </p></div>
|
|
|
|
<p>Zimon et al. (2011) identified a heterozygous R120W substitution in affected members of 3 unrelated families with dominant inheritance of axonal CMT. The families were of Italian, Austrian, and Ashkenazi Jewish descent, respectively. Haplotype analysis indicated a common origin of the mutation, consistent with a founder effect. Expression of the R120W dominant mutation in HeLa cells resulted in impaired mitochondrial fusion, supporting its pathogenicity. The phenotype was considerably variable: age at onset ranged from childhood to adulthood. Walking difficulties were the most common initial symptom and the disorder was slowly progressive, but patients remained ambulatory with mainly distal muscle weakness and atrophy. Two patients also developed proximal weakness. One mutation carrier was asymptomatic, indicating incomplete penetrance. </p>
|
|
|
|
<p>For a discussion of a possible modifier effect on the GDPA1 R120W mutation by a R213P variant in the JPH1 gene, see 605266.0001.</p>
|
|
</span>
|
|
</div>
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2K</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GDAP1, THR157PRO
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894079,
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|
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|
|
|
|
|
ClinVar: RCV000004419, RCV000798174, RCV001533514
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a sporadic case of severe Charcot-Marie-Tooth disease type 2K (CMT2K; see 607831), Claramunt et al. (2005) identified a de novo heterozygous c.469A-C transversion in the GDAP1 gene, resulting in a thr157-to-pro (T157P) substitution. The patient had early onset of symptoms within the first year of life, moderately reduced distal strength in the lower limbs, absent tendon reflexes, and optic atrophy. </p></div>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE A</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
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CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL RECESSIVE, TYPE 2K, INCLUDED
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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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GDAP1, LEU239PHE
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<br />
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SNP: rs104894080,
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gnomAD: rs104894080,
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ClinVar: RCV000004420, RCV000033147, RCV000034153, RCV000414821, RCV000439841, RCV000779562, RCV000789780, RCV002362562, RCV002496254
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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 />
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<p><strong><em>Charcot-Marie-Tooth Disease, Recessive Intermediate A</em></strong>
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</p>
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<div class="mim-changed mim-change"><p>In a 39-year-old woman with recessive intermediate Charcot-Marie-Tooth disease (CMTRIA; 608340), Kabzinska et al. (2006) identified a homozygous c.715C-T transition in exon 6 of the GDAP1 gene, resulting in a leu239-to-phe (L239F) substitution. The patient had early onset of a motor and sensory neuropathy leading to severe disability in the third decade of life. </p></div>
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<p />
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<p><strong><em>Charcot-Marie-Tooth Disease, Type 2K</em></strong>
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</p>
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<p>Kabzinska et al. (2010) identified the L239F mutation, either in homozygous state or in compound heterozygous state with another pathogenic GDAP1 mutation (see, e.g., R282C; 606598.0006), in affected individuals from 4 families and in 2 individual patients, all with early-onset autosomal recessive CMT. Five of the families were Polish and 1 was Bulgarian. The age at onset ranged from 2 to 10 years, and all had gait abnormalities due to lower limb weakness and atrophy. Two patients who were homozygous for the L239F mutation became wheelchair-bound as young adults. Electrophysiologic studies showed that most patients had normal motor and sensory nerve conduction velocities, whereas a few had reduced responses. The diagnosis was autosomal recessive sensorimotor axonal neuropathy (CMT2K; 607831). Haplotype analysis indicated a founder effect for the L239F mutation, indicating that it is prevalent in the Central and Eastern European populations. Kabzinska et al. (2010) observed that the phenotype resulting from this missense mutation was slightly milder than that associated with GDAP1 nonsense mutations (e.g., S194X; 606598.0002). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0012 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2K</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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GDAP1, GLN218GLU
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<br />
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SNP: rs121908113,
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ClinVar: RCV000004421, RCV003447065
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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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<div class="mim-changed mim-change"><p>In a Korean father and daughter with late-onset autosomal dominant axonal Charcot-Marie-Tooth disease type 2K (CMT2K; see 607831), Chung et al. (2008) identified a heterozygous c.652C-G transversion in the GDAP1 gene, resulting in a gln218-to-glu (Q218E) substitution in a highly conserved region of the glutathione S-transferase core region of the protein. The mutation was not identified in 374 control chromosomes. The patients had onset of gait difficulties at age 25 and 16 years, respectively. Other features included hand muscle atrophy, decreased distal sensation in the upper and lower limbs, and normal or mildly reduced nerve conduction velocities. Sural nerve biopsy findings in the father were consistent with a primarily axonal process, but there were also signs of demyelination. The phenotype in this family was much milder than that observed in patients with recessive GDAP1 mutations. </p></div>
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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>.0013 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL RECESSIVE, TYPE 2K</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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GDAP1, PRO231LEU
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<br />
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SNP: rs121908114,
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gnomAD: rs121908114,
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ClinVar: RCV000004422, RCV000214299, RCV000703370, RCV000857208, RCV002362563, RCV005041980
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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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<div class="mim-changed mim-change"><p>In 3 sibs from a consanguineous Amish family with autosomal recessive axonal Charcot-Marie-Tooth disease type 2K (CMT2K; 607831), Xin et al. (2008) identified a homozygous c.692C-T transition in exon 5 of the GDAP1 gene, resulting in a pro231-to-leu (P231L) substitution. The patients had childhood onset of distal lower muscle weakness and borderline nerve conduction velocity measurements, consistent with an axonal neuropathy. The disorder was gradually progressive with worsening of the lower limb symptoms, but the patients were still able to do some daily activities in their twenties. There was no vocal cord or hand muscle involvement. The variant was not seen in 100 control chromosomes from a Lancaster County Amish settlement, but was observed in heterozygosity in 7 (14%) of 50 control individuals from a Geauga County Amish settlement. </p></div>
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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>.0014 CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL DOMINANT, TYPE 2K</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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GDAP1, CYS240TYR
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<br />
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SNP: rs121908115,
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gnomAD: rs121908115,
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|
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ClinVar: RCV000004423, RCV003447066
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In 4 affected members of a French family with autosomal dominant Charcot-Marie-Tooth disease type 2K (CMT2K; see 607831), Cassereau et al. (2009) identified a heterozygous c.719G-A transition in the GDAP1 gene, resulting in a cys240-to-tyr (C240Y) substitution in a conserved residue of the putative GST core region. Mitochondrial respiratory chain complex I activity in patient fibroblasts was 50% lower than controls, but the overall efficiency of ATP production was not affected, indicating compensatory mechanisms. Electron microscopy showed that the tubular mitochondria were 33% larger in diameter and that the mitochondrial mass was 20% greater compared to controls. Cassereau et al. (2009) concluded that, in addition to the regulatory role GDAP1 plays in mitochondrial network dynamics, it may also be involved in energy production and in the control of mitochondrial volume. The authors postulated a dominant-negative effect of the C240Y mutation. </p></div>
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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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL DOMINANT, TYPE 2K</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
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|
|
|
GDAP1, ARG226SER
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<br />
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|
|
SNP: rs267606842,
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|
|
|
ClinVar: RCV000004424, RCV003447067
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In an Italian mother and daughter child with autosomal dominant Charcot-Marie-Tooth disease type 2K (CMT2K; see 607831), Crimella et al. (2010) identified a heterozygous c.678A-T transversion in exon 5 of the GDAP1 gene, resulting in an arg226-to-ser (R226S) substitution in a highly conserved region in the GST domain. The 25-year-old daughter presented with lower limb involvement at age 8 years and retained independent ambulation. The 49-year-old mother had EMG findings of axonal CMT at age 35 years but showed no clinical signs of the disorder. She developed mild lower limb involvement in her late forties. The mutation was not found in 500 controls. The family illustrated significant intrafamilial variability. </p></div>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE A</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GDAP1, GLY327ASP
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs397515432,
|
|
|
|
|
|
|
|
ClinVar: RCV000033148, RCV001055971, RCV003152669, RCV003447102, RCV005049398
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In 2 sisters from a small village in northeast Poland with a mixed form of axonal and demyelinating autosomal recessive Charcot-Marie-Tooth disease (CMTRIA; 608340), Kabzinska et al. (2011) identified a homozygous c.980G-A transition in the GDAP1 gene, resulting in a gly327-to-asp (G327D) substitution in the transmembrane domain, which is important for targeting to the mitochondrial outer membrane. In vitro functional expression studies showed that the mutation interfered with mitochondrial targeting and insertion into the mitochondrial membrane. Cells with overexpression of GDAP1 had a predominantly fragmented mitochondrial morphology, consistent with its role as a mitochondrial fission factor. Cells expressing the G327D mutant protein showed no change in mitochondrial morphology compared to controls, indicating a complete loss of normal fission activity. Kabzinska et al. (2011) commented that this missense GDAP1 mutation resulted in a severe phenotype usually associated with nonsense mutations, and that the complete loss of fission activity on a cellular level correlates with a severe phenotype. </p></div>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL DOMINANT, TYPE 2K</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GDAP1, ALA156GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397515441,
|
|
|
|
|
|
|
|
ClinVar: RCV000043548, RCV002513634
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 2 distantly related Polish families with autosomal dominant Charcot-Marie-Tooth disease type 2K (CMT2K; 607831), Zimon et al. (2011) identified a heterozygous c.467C-G transversion in the GDAP1 gene, resulting in an ala156-to-gly (A156G) substitution at a highly conserved residue. One unaffected family member carried the mutation, consistent with incomplete penetrance. The mutation was not found in 280 control individuals. Expression of this dominant mutation in HeLa cells resulted in impaired mitochondrial fusion, caused mitochondrial fragmentation, and increased cell sensitivity to apoptosis. The patients had onset in the first or second decades of walking difficulties due to distal muscle weakness and atrophy. The disorder was slowly progressive, and all patients remained ambulatory. Nerve conduction velocities showed an axonal pattern. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL DOMINANT, TYPE 2K</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GDAP1, HIS123ARG
|
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|
|
|
<br />
|
|
|
|
SNP: rs397515442,
|
|
|
|
|
|
|
|
ClinVar: RCV000043549, RCV000254797, RCV000696667, RCV000857206
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected members of a large Finnish family with autosomal dominant Charcot-Marie-Tooth disease type 2K (CMT2K; see 607831), Zimon et al. (2011) identified a heterozygous c.358A-G transition in the GDAP1 gene, resulting in a his123-to-arg (H123R) substitution. (The nucleotide numbering was based on a revised transcript.) Four older asymptomatic family members also carried the mutation, indicating incomplete penetrance. The mutation was not found in 280 control individuals. The phenotype was variable, with onset of difficulty walking due to distal muscle weakness and atrophy between 3 and 32 years of age. The disorder was slowly progressive, and all patients remained ambulatory. One patient had proximal weakness. Nerve conduction studies showed an axonal pattern. A heterozygous H123R mutation occurred de novo in a patient of Tunisian origin who was more severely affected and showed delayed motor development; that patient had intermediate results on electrophysiologic studies. </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>.0019 CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL DOMINANT, TYPE 2K</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GDAP1, PRO274LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397515443,
|
|
|
|
|
|
|
|
ClinVar: RCV000043550
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In an Italian father and son with autosomal dominant Charcot-Marie-Tooth disease type 2K (CMT2K; see 607831), Zimon et al. (2011) identified a heterozygous c.821C-T transition in the GDAP1 gene, resulting in a pro274-to-leu (P274L) substitution at a highly conserved residue in the C-terminal GST domain. The mutation was not found in 280 control individuals. The father, who had onset of distal muscle weakness and atrophy at age 47 years and became wheelchair-bound at age 61, had an intermediate pattern on nerve conduction studies. The son was clinically asymptomatic, but showed an axonal pattern on nerve conduction studies. </p></div>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
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<li>
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<p class="mim-text-font">
|
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Baxter, R. V., Ben Othmane, K., Rochelle, J. M., Stajich, J. E., Hulette, C., Dew-Knight, S., Hentati, F., Ben Hamida, M., Bel, S., Stenger, J. E., Gilbert, J. R., Pericak-Vance, M. A., Vance, J. M.
|
|
<strong>Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21.</strong>
|
|
Nature Genet. 30: 21-22, 2002.
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|
[PubMed: 11743579]
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[Full Text: https://doi.org/10.1038/ng796]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Birouk, N., Azzedine, H., Dubourg, O., Muriel, M.-P., Benomar, A., Hamadouche, T., Maisonobe, T., Ouazzani, R., Brice, A., Yahyaoui, M., Chkili, T., LeGuern, E.
|
|
<strong>Phenotypical features of a Moroccan family with autosomal recessive Charcot-Marie-Tooth disease associated with the S194X mutation in the GDAP1 gene.</strong>
|
|
Arch. Neurol. 60: 598-604, 2003.
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|
[PubMed: 12707075]
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[Full Text: https://doi.org/10.1001/archneur.60.4.598]
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</p>
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|
</li>
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<li>
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<p class="mim-text-font">
|
|
Boerkoel, C. F., Takashima, H., Nakagawa, M., Izumo, S., Armstrong, D., Butler, I., Mancias, P., Papasozomenos, S. C. H., Stern, L. Z., Lupski, J. R.
|
|
<strong>CMT4A: identification of a Hispanic GDAP1 founder mutation.</strong>
|
|
Ann. Neurol. 53: 400-405, 2003.
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|
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|
|
[PubMed: 12601710]
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[Full Text: https://doi.org/10.1002/ana.10505]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Cassereau, J., Chevrollier, A., Gueguen, N., Malinge, M.-C., Letournel, F., Nicolas, G., Richard, L., Ferre, M., Verny, C., Dubas, F., Procaccio, V., Amati-Bonneau, P., Bonneau, D., Reynier, P.
|
|
<strong>Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K).</strong>
|
|
Neurogenetics 10: 145-150, 2009.
|
|
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|
|
[PubMed: 19089472]
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|
[Full Text: https://doi.org/10.1007/s10048-008-0166-9]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Chung, K. W., Kim, S. M., Sunwoo, I. N., Cho, S. Y., Hwang, S. J., Kim, J., Kang, S. H., Park, K.-D., Choi, K.-G., Choi, I. S., Choi, B.-O.
|
|
<strong>A novel GDAP1 Q218E mutation in autosomal dominant Charcot-Marie-Tooth disease.</strong>
|
|
J. Hum. Genet. 53: 360-364, 2008.
|
|
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|
|
[PubMed: 18231710]
|
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|
|
[Full Text: https://doi.org/10.1007/s10038-008-0249-3]
|
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</p>
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</div>
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</div>
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</div>
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<div class="modal-footer">
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<button type="button" id="mimDonationPopupDonate" class="btn btn-success btn-block" data-dismiss="modal"> Donate To OMIM! </button>
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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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</body>
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</html>
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