4397 lines
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Entry
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- *608803 - GAP JUNCTION PROTEIN, GAMMA-2; GJC2
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- OMIM
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<p>
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<span class="h4">*608803</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="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/608803">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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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 id="mimExternalLinksFold" class="collapse in">
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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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<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=ENSG00000198835;t=ENST00000366714" 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=57165" 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=608803" 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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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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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=ENSG00000198835;t=ENST00000366714" 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_020435" 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_020435" 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=608803" 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 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=10582&isoform_id=10582_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/GJC2" 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/2738577,27370662,30909115,45439367,58477274,74744875,119590266,182374712" 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/Q5T442" 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 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=57165" 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=ENSG00000198835;t=ENST00000366714" 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=GJC2" 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=GJC2" 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+57165" 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/GJC2" 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:57165" 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/57165" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr1&hgg_gene=ENST00000366714.3&hgg_start=228149930&hgg_end=228159826&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 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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<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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=608803[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=608803[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/GJC2/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/ENSG00000198835" 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.gwascentral.org/search?q=GJC2" 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=GJC2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=GJC2&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/PA162389696" 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:17494" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:2153060" 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/GJC2#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:2153060" 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/57165/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=57165" 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-040912-134" 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=GJC2&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> 870287007<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>
|
|
608803
|
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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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GAP JUNCTION PROTEIN, GAMMA-2; GJC2
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</span>
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</h3>
|
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
GAP JUNCTION PROTEIN, ALPHA 12; GJA12<br />
|
|
GAP JUNCTION PROTEIN, 47-KD<br />
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CONNEXIN 47; CX47<br />
|
|
CONNEXIN 46.6; CX46.6
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=GJC2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GJC2</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/1/1773?start=-3&limit=10&highlight=1773">1q42.13</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:228149930-228159826&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">1:228,149,930-228,159,826</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=613206,608804,613480" 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>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/1773?start=-3&limit=10&highlight=1773">
|
|
1q42.13
|
|
</a>
|
|
</span>
|
|
</td>
|
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|
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|
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<td>
|
|
<span class="mim-font">
|
|
?Spastic paraplegia 44, autosomal recessive
|
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
|
</span>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/613206"> 613206 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<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>
|
|
<td>
|
|
<span class="mim-font">
|
|
Leukodystrophy, hypomyelinating, 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/608804"> 608804 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Lymphatic malformation 3
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/613480"> 613480 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
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|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
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<div>
|
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|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/608803" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/608803" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
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<p>The complete coding sequence of the GJA12 (GJC2) gene has been deposited in GenBank (<a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AF014643" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AF014643</a>). The GJA12 sequence encodes a 436-amino acid protein (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AAB94511" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AAB94511</a>).</p><p><a href="#11" class="mim-tip-reference" title="Orthmann-Murphy, J. L., Enriquez, A. D., Abrams, C. K., Scherer, S. S. <strong>Loss-of-function GJA12/connexin 47 mutations cause Pelizaeus-Merzbacher-like disease.</strong> Molec. Cell. Neurosci. 34: 629-641, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17344063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17344063</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17344063[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.mcn.2007.01.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17344063">Orthmann-Murphy et al. (2007)</a> noted that the GJC2 gene has 2 potential ATG start codons: 1 is located in the 5-prime untranslated region and is 9 nucleotides upstream of the ATG conventionally considered to be the connexin start codon. The protein was found to be expressed on primate oligodendrocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17344063" 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>For background information on connexins, see CX26 (GJB2; <a href="/entry/121011">121011</a>).</p>
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<p>Gap junction proteins are members of a large family of homologous connexins and comprise 4 transmembrane, 2 extracellular, and 3 cytoplasmic domains. They have been identified in a broad range of mammalian tissues, and most tissues expressed more than 1 species of connexin protein. <a href="#8" class="mim-tip-reference" title="Menichella, D. M., Goodenough, D. A., Sirkowski, E., Scherer, S. S., Paul, D. L. <strong>Connexins are critical for normal myelination in the CNS.</strong> J. Neurosci. 23: 5963-5973, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12843301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12843301</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12843301[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/10.1523/JNEUROSCI.23-13-05963.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12843301">Menichella et al. (2003)</a> found that Cx47 (Gja12) is expressed specifically in oligodendrocytes and that its expression is regulated in parallel with other myelin genes. Cx47 and Cx32 (Gjb1; <a href="/entry/304040">304040</a>) partially colocalized in oligodendrocytes, which together with Schwann cells synthesize the multilamellar myelin membranes surrounding axons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12843301" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By RT-PCR analysis, <a href="#16" class="mim-tip-reference" title="Uhlenberg, B., Schuelke, M., Ruschendorf, F., Ruf, N., Kaindl, A. M., Henneke, M., Thiele, H., Stoltenburg-Didinger, G., Aksu, F., Topaloglu, H., Nurnberg, P., Hubner, C., Weschke, B., Gartner, J. <strong>Mutations in the gene encoding gap junction protein alpha-12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.</strong> Am. J. Hum. Genet. 75: 251-260, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 737 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15192806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15192806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15192806[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/10.1086/422763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15192806">Uhlenberg et al. (2004)</a> examined the expression of GJA12 in comparison with that of GJB1. Both were more highly expressed in brain and spinal cord than in peripheral nerve tissue. GJA12 could be amplified from sciatic and sural nerves of healthy adults. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15192806" 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="Uhlenberg, B., Schuelke, M., Ruschendorf, F., Ruf, N., Kaindl, A. M., Henneke, M., Thiele, H., Stoltenburg-Didinger, G., Aksu, F., Topaloglu, H., Nurnberg, P., Hubner, C., Weschke, B., Gartner, J. <strong>Mutations in the gene encoding gap junction protein alpha-12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.</strong> Am. J. Hum. Genet. 75: 251-260, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 737 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15192806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15192806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15192806[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/10.1086/422763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15192806">Uhlenberg et al. (2004)</a> remarked that GJA12 seems to be more important for oligodendrocyte homeostasis than GJB1, which is mutant in X-linked Charcot-Marie-Tooth disease (CMTX1; <a href="/entry/302800">302800</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15192806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The GJA12 gene consists of a single exon (<a href="#16" class="mim-tip-reference" title="Uhlenberg, B., Schuelke, M., Ruschendorf, F., Ruf, N., Kaindl, A. M., Henneke, M., Thiele, H., Stoltenburg-Didinger, G., Aksu, F., Topaloglu, H., Nurnberg, P., Hubner, C., Weschke, B., Gartner, J. <strong>Mutations in the gene encoding gap junction protein alpha-12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.</strong> Am. J. Hum. Genet. 75: 251-260, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 737 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15192806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15192806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15192806[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/10.1086/422763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15192806">Uhlenberg et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15192806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The GJA12 gene maps to chromosome 1q41-q42 (<a href="#16" class="mim-tip-reference" title="Uhlenberg, B., Schuelke, M., Ruschendorf, F., Ruf, N., Kaindl, A. M., Henneke, M., Thiele, H., Stoltenburg-Didinger, G., Aksu, F., Topaloglu, H., Nurnberg, P., Hubner, C., Weschke, B., Gartner, J. <strong>Mutations in the gene encoding gap junction protein alpha-12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.</strong> Am. J. Hum. Genet. 75: 251-260, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 737 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15192806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15192806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15192806[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/10.1086/422763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15192806">Uhlenberg et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15192806" 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="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 2/27/2014."None>Gross (2014)</a> mapped the GJC2 gene to chromosome 1q42.13 based on an alignment of the GJC2 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AF014643" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AF014643</a>) with the genomic sequence (GRCh37).</p>
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In a consanguineous Turkish family and 2 nonconsanguineous German families with autosomal recessive hypomyelinating leukodystrophy (HLD2; <a href="/entry/608804">608804</a>), also designated PMLD1, <a href="#16" class="mim-tip-reference" title="Uhlenberg, B., Schuelke, M., Ruschendorf, F., Ruf, N., Kaindl, A. M., Henneke, M., Thiele, H., Stoltenburg-Didinger, G., Aksu, F., Topaloglu, H., Nurnberg, P., Hubner, C., Weschke, B., Gartner, J. <strong>Mutations in the gene encoding gap junction protein alpha-12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.</strong> Am. J. Hum. Genet. 75: 251-260, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 737 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15192806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15192806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15192806[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/10.1086/422763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15192806">Uhlenberg et al. (2004)</a> identified 5 different GJA12 mutations; they could not find GJA12 mutations in 3 other affected families. As expected, patients from the consanguineous family displayed a homozygous mutation, 857T-C (<a href="#0001">608803.0001</a>). The 2 German families showed compound heterozygous GJA12 mutations. Some patients showed reduced nerve conduction velocities, which indicated the presence of a mild peripheral demyelinating motor neuropathy, predominantly of the lower limbs, consistent with GJA12 expression in sural and sciatic nerve tissue. Since Gjb1 and Gja12 are functionally redundant in mice, <a href="#16" class="mim-tip-reference" title="Uhlenberg, B., Schuelke, M., Ruschendorf, F., Ruf, N., Kaindl, A. M., Henneke, M., Thiele, H., Stoltenburg-Didinger, G., Aksu, F., Topaloglu, H., Nurnberg, P., Hubner, C., Weschke, B., Gartner, J. <strong>Mutations in the gene encoding gap junction protein alpha-12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.</strong> Am. J. Hum. Genet. 75: 251-260, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 737 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15192806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15192806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15192806[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/10.1086/422763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15192806">Uhlenberg et al. (2004)</a> favored the hypothesis that the missense mutants of GJA12 found in their patients with Pelizaeus-Merzbacher-like disease (PMLD) displayed toxic gain of function in oligodendrocytes. <a href="#11" class="mim-tip-reference" title="Orthmann-Murphy, J. L., Enriquez, A. D., Abrams, C. K., Scherer, S. S. <strong>Loss-of-function GJA12/connexin 47 mutations cause Pelizaeus-Merzbacher-like disease.</strong> Molec. Cell. Neurosci. 34: 629-641, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17344063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17344063</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17344063[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.mcn.2007.01.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17344063">Orthmann-Murphy et al. (2007)</a> stated that the alternative ATG start codon used by <a href="#16" class="mim-tip-reference" title="Uhlenberg, B., Schuelke, M., Ruschendorf, F., Ruf, N., Kaindl, A. M., Henneke, M., Thiele, H., Stoltenburg-Didinger, G., Aksu, F., Topaloglu, H., Nurnberg, P., Hubner, C., Weschke, B., Gartner, J. <strong>Mutations in the gene encoding gap junction protein alpha-12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.</strong> Am. J. Hum. Genet. 75: 251-260, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 737 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15192806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15192806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15192806[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/10.1086/422763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15192806">Uhlenberg et al. (2004)</a> is unlikely to be the initiation codon. Thus, the mutations described by <a href="#16" class="mim-tip-reference" title="Uhlenberg, B., Schuelke, M., Ruschendorf, F., Ruf, N., Kaindl, A. M., Henneke, M., Thiele, H., Stoltenburg-Didinger, G., Aksu, F., Topaloglu, H., Nurnberg, P., Hubner, C., Weschke, B., Gartner, J. <strong>Mutations in the gene encoding gap junction protein alpha-12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.</strong> Am. J. Hum. Genet. 75: 251-260, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 737 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15192806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15192806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15192806[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/10.1086/422763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15192806">Uhlenberg et al. (2004)</a> contain 3 additional amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15192806+17344063" 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="Wolf, N. I., Cundall, M., Rutland, P., Rosser, E., Surtees, R., Benton, S., Chong, W. K., Malcolm, S., Ebinger, F., Bitner-Glindzicz, M., Woodward, K. J. <strong>Frameshift mutation in GJA12 leading to nystagmus, spastic ataxia and CNS dys-/demyelination.</strong> Neurogenetics 8: 39-44, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16969684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16969684</a>] [<a href="https://doi.org/10.1007/s10048-006-0062-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16969684">Wolf et al. (2007)</a> identified a homozygous deletion in the GJA12 gene (<a href="#0006">608803.0006</a>) in 2 sibs with hypomyelinating leukodystrophy who were born of consanguineous Pakistani parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16969684" 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="Henneke, M., Combes, P., Diekmann, S., Bertini, E., Brockmann, K., Burlina, A. P., Kaiser, J., Ohlenbusch, A., Plecko, B., Rodriguez, D., Boespflug-Tanguy, O., Gartner, J. <strong>GJA12 mutations are a rare cause of Pelizaeus-Merzbacher-like disease.</strong> Neurology 70: 748-754, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18094336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18094336</a>] [<a href="https://doi.org/10.1212/01.wnl.0000284828.84464.35" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18094336">Henneke et al. (2008)</a> identified 11 mutations (see, e.g., <a href="#0007">608803.0007</a>) in the GJA12 gene in affected members of 14 (7.7%) of 182 families with a PMLD-like phenotype. The authors concluded that GJA12 mutations are not a common cause for a PMLD-like disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18094336" 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="Diekmann, S., Henneke, M., Burckhardt, B. C., Gartner, J. <strong>Pelizaeus-Merzbacher-like disease is caused not only by a loss of connexin47 function but also by a hemichannel dysfunction.</strong> Europ. J. Hum. Genet. 18: 985-992, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20442743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20442743</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20442743[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2010.61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20442743">Diekmann et al. (2010)</a> investigated the in vitro functional effects of 4 different PMLD-like GJC2 mutations in HeLa cells and oligodendrocyte precursors. The mutants thr265-to-ala (T265A) and a complex mutation (A98G_V99insT) were retained in the endoplasmic reticulum (ER), gly149-to-ser (G149S) localized to both the ER and the plasma membrane, and thr398-to-ile (T398I )formed gap junctional plaques at the plasma membrane. Voltage clamp studies showed significantly decreased hemichannel currents for gly236-to-arg (G236R), T265A, and A98G_V99insT. In contrast, T398I revealed hemichannel currents comparable to wildtype, but these channels were dysfunctional under depolarization activation conditions. The findings indicated that PMLD is most often caused by a loss of function, but that channel dysfunction may also occur. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20442743" 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>Spastic Paraplegia 44</em></strong></p><p>
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In 3 affected members of an Italian family with hereditary spastic paraplegia-44 (SPG44; <a href="/entry/613206">613206</a>), <a href="#12" class="mim-tip-reference" title="Orthmann-Murphy, J. L., Salsano, E., Abrams, C. K., Bizzi, A., Uziel, G., Freidin, M. M., Lamantea, E., Zeviani, M., Scherer, S. S., Pareyson, D. <strong>Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations.</strong> Brain 132: 426-438, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19056803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19056803</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19056803[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awn328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19056803">Orthmann-Murphy et al. (2009)</a> identified a homozygous mutation in the GJC2 gene (I33M; <a href="#0008">608803.0008</a>). Heterozygous family members were unaffected. The authors noted that the phenotype was less severe than hypomyelinating leukoencephalopathy-2 (HLD2; <a href="/entry/608804">608804</a>), an allelic disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19056803" 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>Lymphatic Malformation 3</em></strong></p><p>
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In affected members of 2 large families with autosomal dominant lymphatic malformation-3 (LMPHM3; <a href="/entry/613480">613480</a>), <a href="#4" class="mim-tip-reference" title="Ferrell, R. E., Baty, C. J., Kimak, M. A., Karlsson, J. M., Lawrence, E. C., Franke-Snyder, M., Meriney, S. D., Feingold, E., Finegold, D. N. <strong>GJC2 missense mutations cause human lymphedema.</strong> Am. J. Hum. Genet. 86: 943-948, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20537300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20537300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20537300[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.04.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20537300">Ferrell et al. (2010)</a> identified 2 different heterozygous mutations in the GJC2 gene (<a href="#0009">608803.0009</a> and <a href="#0010">608803.0010</a>, respectively). Both mutations affected the extracellular domain. Affected individuals had onset in the first or second decade of uncomplicated lymphedema of the lower limbs, and some later developed upper limb involvement. Incomplete penetrance was observed. <a href="#4" class="mim-tip-reference" title="Ferrell, R. E., Baty, C. J., Kimak, M. A., Karlsson, J. M., Lawrence, E. C., Franke-Snyder, M., Meriney, S. D., Feingold, E., Finegold, D. N. <strong>GJC2 missense mutations cause human lymphedema.</strong> Am. J. Hum. Genet. 86: 943-948, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20537300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20537300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20537300[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.04.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20537300">Ferrell et al. (2010)</a> hypothesized that the mutations may result in impaired channel activity, which may cause impaired coordination of pulsatile lymphatic flow. Four additional putative mutations in the GJC2 gene were identified in 4 smaller families with lymphedema; no functional studies were performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20537300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By linkage analysis followed by whole-exome sequencing, <a href="#14" class="mim-tip-reference" title="Ostergaard, P., Simpson, M. A., Brice, G., Mansour, S., Connell, F. C., Onoufriadis, A., Child, A. H., Hwang, J., Kalidas, K., Mortimer, P. S., Trembath, R., Jeffery, S. <strong>Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype.</strong> J. Med. Genet. 48: 251-255, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21266381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21266381</a>] [<a href="https://doi.org/10.1136/jmg.2010.085563" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21266381">Ostergaard et al. (2011)</a> identified a heterozygous mutation in the GJC2 gene (S48L; <a href="#0009">608803.0009</a>) in 8 affected members of a family with autosomal dominant primary lymphedema. Genetic analysis of an unrelated affected family identified the same pathogenic mutation. Further sequencing of this gene in 19 unrelated individuals with lymphedema identified 3 with mutations in the GJC2 gene, 2 of whom also carried the S48L substitution. <a href="#14" class="mim-tip-reference" title="Ostergaard, P., Simpson, M. A., Brice, G., Mansour, S., Connell, F. C., Onoufriadis, A., Child, A. H., Hwang, J., Kalidas, K., Mortimer, P. S., Trembath, R., Jeffery, S. <strong>Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype.</strong> J. Med. Genet. 48: 251-255, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21266381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21266381</a>] [<a href="https://doi.org/10.1136/jmg.2010.085563" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21266381">Ostergaard et al. (2011)</a> concluded that mutations in GJC2 are a significant cause of autosomal dominant primary lymphedema. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21266381" 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>Gja12 knockout mice are completely Gja12-deficient but clinically normal (<a href="#10" class="mim-tip-reference" title="Odermatt, B., Wellershaus, K., Wallraff, A., Seifert, G., Degen, J., Euwens, C., Fuss, B., Bussow, H., Schilling, K., Steinhauser, C., Willecke, K. <strong>Connexin 47 (Cx47)-deficient mice with enhanced green fluorescent protein reporter gene reveal predominant oligodendrocytic expression of Cx47 and display vacuolized myelin in the CNS.</strong> J. Neurosci. 23: 4549-4559, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12805295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12805295</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12805295[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/10.1523/JNEUROSCI.23-11-04549.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12805295">Odermatt et al., 2003</a>). Mice lacking both Cx47 and Cx32 (Gjb1) develop severe oligodendrocyte death and present with tremor and tonic seizures (<a href="#10" class="mim-tip-reference" title="Odermatt, B., Wellershaus, K., Wallraff, A., Seifert, G., Degen, J., Euwens, C., Fuss, B., Bussow, H., Schilling, K., Steinhauser, C., Willecke, K. <strong>Connexin 47 (Cx47)-deficient mice with enhanced green fluorescent protein reporter gene reveal predominant oligodendrocytic expression of Cx47 and display vacuolized myelin in the CNS.</strong> J. Neurosci. 23: 4549-4559, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12805295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12805295</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12805295[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/10.1523/JNEUROSCI.23-11-04549.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12805295">Odermatt et al., 2003</a>; <a href="#8" class="mim-tip-reference" title="Menichella, D. M., Goodenough, D. A., Sirkowski, E., Scherer, S. S., Paul, D. L. <strong>Connexins are critical for normal myelination in the CNS.</strong> J. Neurosci. 23: 5963-5973, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12843301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12843301</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12843301[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/10.1523/JNEUROSCI.23-13-05963.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12843301">Menichella et al., 2003</a>). By electron microscopy, <a href="#10" class="mim-tip-reference" title="Odermatt, B., Wellershaus, K., Wallraff, A., Seifert, G., Degen, J., Euwens, C., Fuss, B., Bussow, H., Schilling, K., Steinhauser, C., Willecke, K. <strong>Connexin 47 (Cx47)-deficient mice with enhanced green fluorescent protein reporter gene reveal predominant oligodendrocytic expression of Cx47 and display vacuolized myelin in the CNS.</strong> J. Neurosci. 23: 4549-4559, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12805295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12805295</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12805295[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/10.1523/JNEUROSCI.23-11-04549.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12805295">Odermatt et al. (2003)</a> observed conspicuous vacuolation of nerve fibers in central nervous system white matter of Cx47-deficient mice, particularly at the site of the optic nerve where axons are first contacted by oligodendrocytes and myelination starts. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12805295+12843301" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a consanguineous Turkish family, <a href="#16" class="mim-tip-reference" title="Uhlenberg, B., Schuelke, M., Ruschendorf, F., Ruf, N., Kaindl, A. M., Henneke, M., Thiele, H., Stoltenburg-Didinger, G., Aksu, F., Topaloglu, H., Nurnberg, P., Hubner, C., Weschke, B., Gartner, J. <strong>Mutations in the gene encoding gap junction protein alpha-12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.</strong> Am. J. Hum. Genet. 75: 251-260, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 737 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15192806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15192806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15192806[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/10.1086/422763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15192806">Uhlenberg et al. (2004)</a> found that members with autosomal recessive hypomyelinating leukodystrophy (HLD2; <a href="/entry/608804">608804</a>) were homozygous for a T-to-C transition at cDNA position 857 of the GJA12 gene that was predicted to result in a met286-to-thr amino acid substitution (M286T). Three affected members had seizures. Unaided walking was never achieved by 2 and, at age 5, was achieved by a third affected member. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15192806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Orthmann-Murphy, J. L., Enriquez, A. D., Abrams, C. K., Scherer, S. S. <strong>Loss-of-function GJA12/connexin 47 mutations cause Pelizaeus-Merzbacher-like disease.</strong> Molec. Cell. Neurosci. 34: 629-641, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17344063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17344063</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17344063[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.mcn.2007.01.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17344063">Orthmann-Murphy et al. (2007)</a> stated that this mutation is MET283THR (M283T), when using a different ATG initiation codon. Expression of the mutant M283T protein in HeLa cells showed that the mutant protein partially accumulated in the endoplasmic reticulum, although some was expressed at the cell membrane. Mutant protein that formed membrane puncta did not form functional gap junctions, consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17344063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315312 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315312;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/rs74315312?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=rs74315312" 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=rs74315312" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a nonconsanguineous German family, <a href="#16" class="mim-tip-reference" title="Uhlenberg, B., Schuelke, M., Ruschendorf, F., Ruf, N., Kaindl, A. M., Henneke, M., Thiele, H., Stoltenburg-Didinger, G., Aksu, F., Topaloglu, H., Nurnberg, P., Hubner, C., Weschke, B., Gartner, J. <strong>Mutations in the gene encoding gap junction protein alpha-12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.</strong> Am. J. Hum. Genet. 75: 251-260, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 737 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15192806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15192806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15192806[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/10.1086/422763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15192806">Uhlenberg et al. (2004)</a> found that a child with autosomal recessive hypomyelinating leukodystrophy (HLD2; <a href="/entry/608804">608804</a>) was compound heterozygous for a C-to-T transition at cDNA position 268 of the GJA12 gene on the paternal allele, predicted to result in a pro90-to-ser amino acid substitution (P90S), and a single-basepair deletion (989delC; <a href="#0003">608803.0003</a>) on the maternal allele, leading to a frameshift and a nonsense peptide of 141 amino acids after amino acid 329 (cysteine). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15192806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Orthmann-Murphy, J. L., Enriquez, A. D., Abrams, C. K., Scherer, S. S. <strong>Loss-of-function GJA12/connexin 47 mutations cause Pelizaeus-Merzbacher-like disease.</strong> Molec. Cell. Neurosci. 34: 629-641, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17344063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17344063</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17344063[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.mcn.2007.01.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17344063">Orthmann-Murphy et al. (2007)</a> stated that this mutation is PRO87SER (P87S), when using a different ATG initiation codon. Expression of the mutant P87S protein in HeLa cells showed that most of the mutant protein accumulated in the endoplasmic reticulum and failed to form functional gap junctions, consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17344063" 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 LEUKODYSTROPHY, HYPOMYELINATING, 2</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">rs796065027 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs796065027;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=rs796065027" 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=rs796065027" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the 1-bp deletion in the GJC2 gene (989delC) that was found in compound heterozygous state in a patient with autosomal recessive hypomyelinating leukodystrophy (HLD2; <a href="/entry/608804">608804</a>) by <a href="#16" class="mim-tip-reference" title="Uhlenberg, B., Schuelke, M., Ruschendorf, F., Ruf, N., Kaindl, A. M., Henneke, M., Thiele, H., Stoltenburg-Didinger, G., Aksu, F., Topaloglu, H., Nurnberg, P., Hubner, C., Weschke, B., Gartner, J. <strong>Mutations in the gene encoding gap junction protein alpha-12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.</strong> Am. J. Hum. Genet. 75: 251-260, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 737 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15192806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15192806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15192806[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/10.1086/422763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15192806">Uhlenberg et al. (2004)</a>, see <a href="#0002">608803.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15192806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315313 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315313;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/rs74315313?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=rs74315313" 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=rs74315313" 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=RCV000002155 OR RCV001723533" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002155, RCV001723533" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002155...</a>
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<p>In a nonconsanguineous German family, <a href="#16" class="mim-tip-reference" title="Uhlenberg, B., Schuelke, M., Ruschendorf, F., Ruf, N., Kaindl, A. M., Henneke, M., Thiele, H., Stoltenburg-Didinger, G., Aksu, F., Topaloglu, H., Nurnberg, P., Hubner, C., Weschke, B., Gartner, J. <strong>Mutations in the gene encoding gap junction protein alpha-12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.</strong> Am. J. Hum. Genet. 75: 251-260, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 737 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15192806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15192806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15192806[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/10.1086/422763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15192806">Uhlenberg et al. (2004)</a> studied a patient with autosomal recessive hypomyelinating leukodystrophy (HLD2; <a href="/entry/608804">608804</a>) and found compound heterozygosity for 2 mutations in the GJC2 gene: a C-to-T transition at cDNA position 718 on the paternal allele representing a nonsense mutation (R240X), and a T-to-G transversion at cDNA position 814 on the maternal allele, leading to replacement of tyrosine by aspartic acid (Y272D; <a href="#0005">608803.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15192806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using the ATG initiation codon cited by <a href="#11" class="mim-tip-reference" title="Orthmann-Murphy, J. L., Enriquez, A. D., Abrams, C. K., Scherer, S. S. <strong>Loss-of-function GJA12/connexin 47 mutations cause Pelizaeus-Merzbacher-like disease.</strong> Molec. Cell. Neurosci. 34: 629-641, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17344063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17344063</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17344063[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.mcn.2007.01.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17344063">Orthmann-Murphy et al. (2007)</a>, this mutation would be ARG237TER (R237X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17344063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315314 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315314;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/rs74315314?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=rs74315314" 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=rs74315314" 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=RCV000002156" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002156" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002156</a>
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<p>For discussion of the tyr272-to-asp (Y272D) mutation in the GJC2 gene that was found in compound heterozygous state in a patient with autosomal recessive hypomyelinating leukodystrophy (HLD2; <a href="/entry/608804">608804</a>) by <a href="#16" class="mim-tip-reference" title="Uhlenberg, B., Schuelke, M., Ruschendorf, F., Ruf, N., Kaindl, A. M., Henneke, M., Thiele, H., Stoltenburg-Didinger, G., Aksu, F., Topaloglu, H., Nurnberg, P., Hubner, C., Weschke, B., Gartner, J. <strong>Mutations in the gene encoding gap junction protein alpha-12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.</strong> Am. J. Hum. Genet. 75: 251-260, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 737 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15192806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15192806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15192806[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/10.1086/422763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15192806">Uhlenberg et al. (2004)</a>, see <a href="#0004">608803.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15192806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Orthmann-Murphy, J. L., Enriquez, A. D., Abrams, C. K., Scherer, S. S. <strong>Loss-of-function GJA12/connexin 47 mutations cause Pelizaeus-Merzbacher-like disease.</strong> Molec. Cell. Neurosci. 34: 629-641, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17344063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17344063</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17344063[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.mcn.2007.01.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17344063">Orthmann-Murphy et al. (2007)</a> stated that this mutation is TYR269ASP (Y269D), when using a different ATG initiation codon. Expression of the mutant Y269D protein in HeLa cells showed that most of the mutant protein accumulated in the endoplasmic reticulum and failed to form functional gap junctions, consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17344063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs796065028 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs796065028;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=rs796065028" 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=rs796065028" 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=RCV000002157 OR RCV001781168" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002157, RCV001781168" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002157...</a>
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<p>In 2 sibs, born of consanguineous Pakistani parents, with autosomal recessive hypomyelinating leukodystrophy (HLD2; <a href="/entry/608804">608804</a>), <a href="#17" class="mim-tip-reference" title="Wolf, N. I., Cundall, M., Rutland, P., Rosser, E., Surtees, R., Benton, S., Chong, W. K., Malcolm, S., Ebinger, F., Bitner-Glindzicz, M., Woodward, K. J. <strong>Frameshift mutation in GJA12 leading to nystagmus, spastic ataxia and CNS dys-/demyelination.</strong> Neurogenetics 8: 39-44, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16969684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16969684</a>] [<a href="https://doi.org/10.1007/s10048-006-0062-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16969684">Wolf et al. (2007)</a> identified a homozygous 34-bp deletion in the GJA12 gene (del914-947), resulting in a frameshift and a truncated 154-residue peptide. Direct sequencing showed that the deletion was flanked by a 13-bp repeat sequence that may have contributed to formation of the deletion. The 2 sibs showed different clinical phenotypes. The older developed nystagmus at age 4 months, ataxia at 2 years, and spasticity at 6 years. The spasticity progressed, and she was wheelchair-bound by age 16 years. Her younger brother showed nystagmus at age 4 weeks as well as moderately impaired psychomotor development, and was never able to walk independently. He also had a severe sensory neuropathy, which may not have been related to the disorder. Both showed mainly dysmyelination in addition to progressive demyelination on brain MRI. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16969684" 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="Salviati, L., Trevisson, E., Baldoin, M. C., Toldo, I., Sartori, S., Calderone, M., Tenconi, R., Laverda, A. M. <strong>A novel deletion in the GJA12 gene causes Pelizaeus-Merzbacher-like disease.</strong> Neurogenetics 8: 57-60, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17031678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17031678</a>] [<a href="https://doi.org/10.1007/s10048-006-0065-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17031678">Salviati et al. (2007)</a> reported the same homozygous 34-bp deletion (del914-947) in another affected Pakistani girl. Both unaffected parents carried the deletion and denied consanguinity. The deletion was not identified in 200 control alleles. <a href="#15" class="mim-tip-reference" title="Salviati, L., Trevisson, E., Baldoin, M. C., Toldo, I., Sartori, S., Calderone, M., Tenconi, R., Laverda, A. M. <strong>A novel deletion in the GJA12 gene causes Pelizaeus-Merzbacher-like disease.</strong> Neurogenetics 8: 57-60, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17031678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17031678</a>] [<a href="https://doi.org/10.1007/s10048-006-0065-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17031678">Salviati et al. (2007)</a> suggested a loss-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17031678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs796065029 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs796065029;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=rs796065029" 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=rs796065029" 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=RCV000002158" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002158" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002158</a>
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<p>In affected members of 2 presumably unrelated Algerian families with hypomyelinating leukodystrophy (HLD2; <a href="/entry/608804">608804</a>), <a href="#7" class="mim-tip-reference" title="Henneke, M., Combes, P., Diekmann, S., Bertini, E., Brockmann, K., Burlina, A. P., Kaiser, J., Ohlenbusch, A., Plecko, B., Rodriguez, D., Boespflug-Tanguy, O., Gartner, J. <strong>GJA12 mutations are a rare cause of Pelizaeus-Merzbacher-like disease.</strong> Neurology 70: 748-754, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18094336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18094336</a>] [<a href="https://doi.org/10.1212/01.wnl.0000284828.84464.35" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18094336">Henneke et al. (2008)</a> identified a homozygous 1-bp insertion (695insG) in the GJC2 gene, resulting in a frameshift and premature termination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18094336" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs75469429 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs75469429;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/rs75469429?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=rs75469429" 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=rs75469429" 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=RCV000002159" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002159" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002159</a>
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<p>In 3 affected members of an Italian family with spastic paraplegia-44 (SPG44; <a href="/entry/613206">613206</a>), <a href="#12" class="mim-tip-reference" title="Orthmann-Murphy, J. L., Salsano, E., Abrams, C. K., Bizzi, A., Uziel, G., Freidin, M. M., Lamantea, E., Zeviani, M., Scherer, S. S., Pareyson, D. <strong>Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations.</strong> Brain 132: 426-438, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19056803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19056803</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19056803[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awn328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19056803">Orthmann-Murphy et al. (2009)</a> identified a homozygous 99C-G transversion in the GJC2 gene, resulting in an ile33-to-met (I33M) substitution in a highly conserved region in the first transmembrane domain. The mutation was not found in 210 control alleles. In vitro functional expression assays showed that I33M-mutant protein was able to form gap junctions at apposed cell borders and was present at the cell membrane, but homotypic gap junction channels were not functional. I33M-mutant protein was also able to form heteromeric channels with wildtype Cx43 (GJA1; <a href="/entry/121014">121014</a>), but the channels opened only when a large voltage difference that would not be seen under physiologic conditions was applied. Since the mutation resulted in loss of channel function, <a href="#12" class="mim-tip-reference" title="Orthmann-Murphy, J. L., Salsano, E., Abrams, C. K., Bizzi, A., Uziel, G., Freidin, M. M., Lamantea, E., Zeviani, M., Scherer, S. S., Pareyson, D. <strong>Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations.</strong> Brain 132: 426-438, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19056803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19056803</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19056803[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awn328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19056803">Orthmann-Murphy et al. (2009)</a> suggested that the comparatively milder phenotype compared to HLD2 (<a href="/entry/608804">608804</a>) must be due to another functional mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19056803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606847 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606847;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=rs267606847" 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=rs267606847" 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=RCV000002160" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002160" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002160</a>
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<p>In multiple affected members of a large 3-generation family with autosomal dominant hereditary lymphedema (LMPHM3; <a href="/entry/613480">613480</a>), <a href="#4" class="mim-tip-reference" title="Ferrell, R. E., Baty, C. J., Kimak, M. A., Karlsson, J. M., Lawrence, E. C., Franke-Snyder, M., Meriney, S. D., Feingold, E., Finegold, D. N. <strong>GJC2 missense mutations cause human lymphedema.</strong> Am. J. Hum. Genet. 86: 943-948, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20537300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20537300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20537300[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.04.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20537300">Ferrell et al. (2010)</a> identified a heterozygous 143C-T transition in the GJC2 gene, resulting in a ser48-to-leu (S48L) substitution in a highly conserved residue in extracellular loop 1. The mutation was not found in 500 control alleles. Affected individuals had early onset, between 0 and 15 years of age, of uncomplicated lymphedema of the lower limbs, and some later developed upper limb involvement. Four individuals had recurrent skin infections. Incomplete penetrance was observed. <a href="#4" class="mim-tip-reference" title="Ferrell, R. E., Baty, C. J., Kimak, M. A., Karlsson, J. M., Lawrence, E. C., Franke-Snyder, M., Meriney, S. D., Feingold, E., Finegold, D. N. <strong>GJC2 missense mutations cause human lymphedema.</strong> Am. J. Hum. Genet. 86: 943-948, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20537300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20537300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20537300[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.04.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20537300">Ferrell et al. (2010)</a> hypothesized that the mutation may result in impaired channel activity, which may cause impaired coordination of pulsatile lymphatic flow. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20537300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Ostergaard, P., Simpson, M. A., Brice, G., Mansour, S., Connell, F. C., Onoufriadis, A., Child, A. H., Hwang, J., Kalidas, K., Mortimer, P. S., Trembath, R., Jeffery, S. <strong>Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype.</strong> J. Med. Genet. 48: 251-255, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21266381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21266381</a>] [<a href="https://doi.org/10.1136/jmg.2010.085563" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21266381">Ostergaard et al. (2011)</a> identified a heterozygous S48L mutation in affected members of 4 additional families with LMPHM3. One of the families was of Somali origin. The phenotype was similar to that observed by <a href="#4" class="mim-tip-reference" title="Ferrell, R. E., Baty, C. J., Kimak, M. A., Karlsson, J. M., Lawrence, E. C., Franke-Snyder, M., Meriney, S. D., Feingold, E., Finegold, D. N. <strong>GJC2 missense mutations cause human lymphedema.</strong> Am. J. Hum. Genet. 86: 943-948, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20537300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20537300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20537300[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.04.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20537300">Ferrell et al. (2010)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21266381+20537300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606846 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606846;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=rs267606846" 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=rs267606846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In multiple affected members of a large 3-generation family with autosomal dominant hereditary lymphedema (LMPHM3; <a href="/entry/613480">613480</a>), <a href="#4" class="mim-tip-reference" title="Ferrell, R. E., Baty, C. J., Kimak, M. A., Karlsson, J. M., Lawrence, E. C., Franke-Snyder, M., Meriney, S. D., Feingold, E., Finegold, D. N. <strong>GJC2 missense mutations cause human lymphedema.</strong> Am. J. Hum. Genet. 86: 943-948, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20537300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20537300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20537300[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.04.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20537300">Ferrell et al. (2010)</a> identified a heterozygous 778C-T transition in the GJC2 gene, resulting in an arg260-to-cys (R260C) substitution in a highly conserved residue in extracellular loop 2. The mutation occurred in the conserved SRPTEK motif, important for connexon docking. The mutation was not found in 500 control alleles. Affected individuals had onset between 10 and 21 years of uncomplicated lymphedema of the lower limbs with upper limb involvement developing later in some. Two patients had cellulitis. Incomplete penetrance was observed. <a href="#4" class="mim-tip-reference" title="Ferrell, R. E., Baty, C. J., Kimak, M. A., Karlsson, J. M., Lawrence, E. C., Franke-Snyder, M., Meriney, S. D., Feingold, E., Finegold, D. N. <strong>GJC2 missense mutations cause human lymphedema.</strong> Am. J. Hum. Genet. 86: 943-948, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20537300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20537300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20537300[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.04.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20537300">Ferrell et al. (2010)</a> hypothesized that the mutation may result in impaired channel activity, which may cause impaired coordination of pulsatile lymphatic flow. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20537300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776888 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776888;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=rs587776888" 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=rs587776888" 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=RCV000023738 OR RCV000633051 OR RCV001781305" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023738, RCV000633051, RCV001781305" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023738...</a>
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<p>In a Japanese female with a mild Pelizaeus-Merzbacher-like disorder (HLD2; <a href="/entry/608804">608804</a>) who was previously reported by <a href="#9" class="mim-tip-reference" title="Nezu, A., Kimura, S., Uehara, S., Osaka, H., Kobayashi, T., Haraguchi, M., Inoue, K., Kawanishi, C. <strong>Pelizaeus-Merzbacher-like disease: female case report.</strong> Brain Dev. 18: 114-118, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8733901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8733901</a>] [<a href="https://doi.org/10.1016/0387-7604(95)00078-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8733901">Nezu et al. (1996)</a>, <a href="#13" class="mim-tip-reference" title="Osaka, H., Hamanoue, H., Yamamoto, R., Nezu, A., Sasaki, M., Saitsu, H., Kurosawa, K., Shimbo, H., Matsumoto, N., Inoue, K. <strong>Disrupted SOX10 regulation of GJC2 transcription causes Pelizaeus-Merzbacher-like disease.</strong> Ann. Neurol. 68: 250-254, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20695017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20695017</a>] [<a href="https://doi.org/10.1002/ana.22022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20695017">Osaka et al. (2010)</a> identified a homozygous -167A-G mutation within the proximal GJC2 promoter that segregated with the disorder. The patient's healthy, second-cousin parents were heterozygous for the mutation, which was not found in 122 normal Japanese chromosomes. The mutation is located within a critical SOX10 binding site (site D) in the syntenic mouse Gjc2 proximal promoter and diminishes the consensus of the SOX binding sequence. Functional studies on the mouse promoter indicated that the -167A-G mutation abolishes SOX10 binding to the GJC2 promoter, resulting in a dramatic attenuation of GJC2 transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8733901+20695017" 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="#2" class="mim-tip-reference" title="Combes, P., Kammoun, N., Monnier, A., Gonthier-Gueret, C., Giraud, G., Bertini, E., Chahnez, T., Fakhfakh, F., Boespflug-Tanguy, O., Vaurs-Barriere, C. <strong>Relevance of GJC2 promoter mutation in Pelizaeus-Merzbacher-like disease.</strong> Ann. Neurol. 71: 146-148, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21246605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21246605</a>] [<a href="https://doi.org/10.1002/ana.22295" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21246605">Combes et al. (2012)</a> identified the -167A-G mutation in 7 patients with a disorder similar to that in the Japanese patient reported by <a href="#13" class="mim-tip-reference" title="Osaka, H., Hamanoue, H., Yamamoto, R., Nezu, A., Sasaki, M., Saitsu, H., Kurosawa, K., Shimbo, H., Matsumoto, N., Inoue, K. <strong>Disrupted SOX10 regulation of GJC2 transcription causes Pelizaeus-Merzbacher-like disease.</strong> Ann. Neurol. 68: 250-254, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20695017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20695017</a>] [<a href="https://doi.org/10.1002/ana.22022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20695017">Osaka et al. (2010)</a>. The mutation was homozygous in 5 patients from 4 unrelated families from the same area of south Tunisia and segregated with the disease in a consanguineous family with 2 affected members; it was also found in 2 unrelated patients from the Mediterranean area in compound heterozygosity with another mutation in the GJC2 gene that had been identified by <a href="#7" class="mim-tip-reference" title="Henneke, M., Combes, P., Diekmann, S., Bertini, E., Brockmann, K., Burlina, A. P., Kaiser, J., Ohlenbusch, A., Plecko, B., Rodriguez, D., Boespflug-Tanguy, O., Gartner, J. <strong>GJA12 mutations are a rare cause of Pelizaeus-Merzbacher-like disease.</strong> Neurology 70: 748-754, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18094336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18094336</a>] [<a href="https://doi.org/10.1212/01.wnl.0000284828.84464.35" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18094336">Henneke et al. (2008)</a> in patients with HLD2. The mutation was not found in 212 healthy individuals from the same geographic regions. Functional studies in COS-7 and HEK293 cells demonstrated a higher luciferase expression with the mutated promoter than with the wildtype, suggesting a possible difference in transcription factor recruitment. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18094336+21246605+20695017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a new reporter luciferase assay in a human glioblastoma cell line (U138), <a href="#5" class="mim-tip-reference" title="Gotoh, L., Inoue, K., Helman, G., Mora, S., Maski, K., Soul, J. S., Bloom, M., Evans, S. H., Goto, Y., Caldovic, L., Hobson, G. M., Vanderver, A. <strong>GJC2 promoter mutations causing Pelizaeus-Merzbacher-like disease.</strong> Molec. Genet. Metab. 111: 393-398, 2014. Note: Erratum: Molec. Genet. Metab. 119: 293 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24374284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24374284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24374284[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ymgme.2013.12.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24374284">Gotoh et al. (2014)</a> demonstrated that the -167A-G mutation reduced transcriptional activity compared to wildtype in response to SOX10 (<a href="/entry/602229">602229</a>). The findings suggested that the mutation disrupts SOX10 binding, resulting in a decrease in the GJC2 expression that is important for the maintenance of myelinating oligodendrocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24374284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514734 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514734;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=rs397514734" 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=rs397514734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a girl, born of consanguineous Sri Lankan parents, with a severe form of hypomyelinating leukodystrophy-2 (HLD2; <a href="/entry/608804">608804</a>), <a href="#1" class="mim-tip-reference" title="Biancheri, R., Rosano, C., Denegri, L., Lamantea, E., Pinto, F., Lanza, F., Severino, M., Filocamo, M. <strong>Expanded spectrum of Pelizaeus-Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form.</strong> Europ. J. Hum. Genet. 21: 34-39, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22669416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22669416</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22669416[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2012.93" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22669416">Biancheri et al. (2013)</a> identified a homozygous c.787G-A transition in the GJC2 gene, resulting in a glu263-to-lys (E263K) substitution at a highly conserved residue in the extracellular loop-2 domain. (<a href="#1" class="mim-tip-reference" title="Biancheri, R., Rosano, C., Denegri, L., Lamantea, E., Pinto, F., Lanza, F., Severino, M., Filocamo, M. <strong>Expanded spectrum of Pelizaeus-Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form.</strong> Europ. J. Hum. Genet. 21: 34-39, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22669416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22669416</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22669416[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2012.93" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22669416">Biancheri et al. (2013)</a> cited the mutation as c.778G-A, resulting in a glu260-to-lys (E260) substitution, based on a different numbering system.) The unaffected parents were heterozygous for the mutation, which was not found in 100 control alleles or in a large control database. Structural analysis predicted that the mutation would disrupt a salt bridge network and hamper correct pore formation and assembly. At birth the patient was noted to have nystagmus, and she subsequently showed severely delayed psychomotor development. Examination at age 7 months showed axial hypotonia, absent head control, increased muscle tone in the lower limbs, and brisk tendon reflexes. Neurophysiologic studies showed abnormal brainstem auditory evoked and visual evoked potentials. Brain MRI showed diffuse hyperintensity on T2-weighted images of the cerebral and cerebellar white matter, including the middle cerebellar peduncles and almost the entire brainstem. The white matter of the cervical spinal cord was also abnormal. At age 5 years, she had not acquired any motor milestones and was severely disabled with spasticity, mental retardation, and poor speech. Funduscopy showed optic atrophy. <a href="#1" class="mim-tip-reference" title="Biancheri, R., Rosano, C., Denegri, L., Lamantea, E., Pinto, F., Lanza, F., Severino, M., Filocamo, M. <strong>Expanded spectrum of Pelizaeus-Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form.</strong> Europ. J. Hum. Genet. 21: 34-39, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22669416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22669416</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22669416[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2012.93" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22669416">Biancheri et al. (2013)</a> noted that the phenotype in this patient was consistent with the connatal form of Pelizaeus-Merzbacher disease (PMD). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22669416" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 LEUKODYSTROPHY, HYPOMYELINATING, 2</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">rs587777496 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777496;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=rs587777496" 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=rs587777496" 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=RCV000128464 OR RCV001849914" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000128464, RCV001849914" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000128464...</a>
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<p>In 2 unrelated patients with hypomyelinating leukodystrophy-2 (HLD2; <a href="/entry/608804">608804</a>), <a href="#5" class="mim-tip-reference" title="Gotoh, L., Inoue, K., Helman, G., Mora, S., Maski, K., Soul, J. S., Bloom, M., Evans, S. H., Goto, Y., Caldovic, L., Hobson, G. M., Vanderver, A. <strong>GJC2 promoter mutations causing Pelizaeus-Merzbacher-like disease.</strong> Molec. Genet. Metab. 111: 393-398, 2014. Note: Erratum: Molec. Genet. Metab. 119: 293 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24374284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24374284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24374284[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ymgme.2013.12.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24374284">Gotoh et al. (2014)</a> identified a homozygous c.-170A-G transition in the promoter region of the GJC2 gene at a conserved residue within the SOX10 (<a href="/entry/602229">602229</a>) transcription factor binding site. Parental DNA was not available, but an unaffected sib of 1 of the patients was heterozygous for the mutation, which was not found in the dbSNP (build 139) or 1000 Genomes Project databases. The patients were of Portuguese and Polish descent, respectively. In vitro functional expression in a human glioblastoma cell line (U138) showed that activation by SOX10 was significantly decreased compared to wildtype. Studies in non-glial cells did not yield as significant a difference. The findings suggested that the mutation disrupts SOX10 binding, resulting in a decrease in the GJC2 expression that is important for the maintenance of myelinating oligodendrocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24374284" 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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Biancheri, R., Rosano, C., Denegri, L., Lamantea, E., Pinto, F., Lanza, F., Severino, M., Filocamo, M.
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<strong>Expanded spectrum of Pelizaeus-Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form.</strong>
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Europ. J. Hum. Genet. 21: 34-39, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22669416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22669416</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22669416[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=22669416" 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/ejhg.2012.93" target="_blank">Full Text</a>]
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Combes, P., Kammoun, N., Monnier, A., Gonthier-Gueret, C., Giraud, G., Bertini, E., Chahnez, T., Fakhfakh, F., Boespflug-Tanguy, O., Vaurs-Barriere, C.
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<strong>Relevance of GJC2 promoter mutation in Pelizaeus-Merzbacher-like disease.</strong>
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Ann. Neurol. 71: 146-148, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21246605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21246605</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21246605" 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.22295" target="_blank">Full Text</a>]
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Diekmann, S., Henneke, M., Burckhardt, B. C., Gartner, J.
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<strong>Pelizaeus-Merzbacher-like disease is caused not only by a loss of connexin47 function but also by a hemichannel dysfunction.</strong>
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Europ. J. Hum. Genet. 18: 985-992, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20442743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20442743</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20442743[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=20442743" 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/ejhg.2010.61" target="_blank">Full Text</a>]
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Ferrell, R. E., Baty, C. J., Kimak, M. A., Karlsson, J. M., Lawrence, E. C., Franke-Snyder, M., Meriney, S. D., Feingold, E., Finegold, D. N.
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<strong>GJC2 missense mutations cause human lymphedema.</strong>
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Am. J. Hum. Genet. 86: 943-948, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20537300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20537300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20537300[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=20537300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2010.04.010" target="_blank">Full Text</a>]
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Gotoh, L., Inoue, K., Helman, G., Mora, S., Maski, K., Soul, J. S., Bloom, M., Evans, S. H., Goto, Y., Caldovic, L., Hobson, G. M., Vanderver, A.
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<strong>GJC2 promoter mutations causing Pelizaeus-Merzbacher-like disease.</strong>
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Molec. Genet. Metab. 111: 393-398, 2014. Note: Erratum: Molec. Genet. Metab. 119: 293 only, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24374284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24374284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24374284[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=24374284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2013.12.001" target="_blank">Full Text</a>]
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Gross, M. B.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 2/27/2014.
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Henneke, M., Combes, P., Diekmann, S., Bertini, E., Brockmann, K., Burlina, A. P., Kaiser, J., Ohlenbusch, A., Plecko, B., Rodriguez, D., Boespflug-Tanguy, O., Gartner, J.
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<strong>GJA12 mutations are a rare cause of Pelizaeus-Merzbacher-like disease.</strong>
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Neurology 70: 748-754, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18094336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18094336</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18094336" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000284828.84464.35" target="_blank">Full Text</a>]
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Menichella, D. M., Goodenough, D. A., Sirkowski, E., Scherer, S. S., Paul, D. L.
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<strong>Connexins are critical for normal myelination in the CNS.</strong>
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J. Neurosci. 23: 5963-5973, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12843301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12843301</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12843301[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=12843301" 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/10.1523/JNEUROSCI.23-13-05963.2003" target="_blank">Full Text</a>]
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Nezu, A., Kimura, S., Uehara, S., Osaka, H., Kobayashi, T., Haraguchi, M., Inoue, K., Kawanishi, C.
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<strong>Pelizaeus-Merzbacher-like disease: female case report.</strong>
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Brain Dev. 18: 114-118, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8733901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8733901</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8733901" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0387-7604(95)00078-x" target="_blank">Full Text</a>]
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<a id="10" class="mim-anchor"></a>
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<a id="Odermatt2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Odermatt, B., Wellershaus, K., Wallraff, A., Seifert, G., Degen, J., Euwens, C., Fuss, B., Bussow, H., Schilling, K., Steinhauser, C., Willecke, K.
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|
<strong>Connexin 47 (Cx47)-deficient mice with enhanced green fluorescent protein reporter gene reveal predominant oligodendrocytic expression of Cx47 and display vacuolized myelin in the CNS.</strong>
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J. Neurosci. 23: 4549-4559, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12805295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12805295</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12805295[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=12805295" 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/10.1523/JNEUROSCI.23-11-04549.2003" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Orthmann-Murphy2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Orthmann-Murphy, J. L., Enriquez, A. D., Abrams, C. K., Scherer, S. S.
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|
<strong>Loss-of-function GJA12/connexin 47 mutations cause Pelizaeus-Merzbacher-like disease.</strong>
|
|
Molec. Cell. Neurosci. 34: 629-641, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17344063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17344063</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17344063[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=17344063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.mcn.2007.01.010" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Orthmann-Murphy2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Orthmann-Murphy, J. L., Salsano, E., Abrams, C. K., Bizzi, A., Uziel, G., Freidin, M. M., Lamantea, E., Zeviani, M., Scherer, S. S., Pareyson, D.
|
|
<strong>Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations.</strong>
|
|
Brain 132: 426-438, 2009.
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|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19056803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19056803</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19056803[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=19056803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awn328" target="_blank">Full Text</a>]
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</p>
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<a id="13" class="mim-anchor"></a>
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<a id="Osaka2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Osaka, H., Hamanoue, H., Yamamoto, R., Nezu, A., Sasaki, M., Saitsu, H., Kurosawa, K., Shimbo, H., Matsumoto, N., Inoue, K.
|
|
<strong>Disrupted SOX10 regulation of GJC2 transcription causes Pelizaeus-Merzbacher-like disease.</strong>
|
|
Ann. Neurol. 68: 250-254, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20695017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20695017</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20695017" 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.22022" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Ostergaard2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ostergaard, P., Simpson, M. A., Brice, G., Mansour, S., Connell, F. C., Onoufriadis, A., Child, A. H., Hwang, J., Kalidas, K., Mortimer, P. S., Trembath, R., Jeffery, S.
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<strong>Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype.</strong>
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J. Med. Genet. 48: 251-255, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21266381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21266381</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21266381" 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.2010.085563" target="_blank">Full Text</a>]
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</p>
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</li>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Salviati2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Salviati, L., Trevisson, E., Baldoin, M. C., Toldo, I., Sartori, S., Calderone, M., Tenconi, R., Laverda, A. M.
|
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<strong>A novel deletion in the GJA12 gene causes Pelizaeus-Merzbacher-like disease.</strong>
|
|
Neurogenetics 8: 57-60, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17031678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17031678</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17031678" 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/s10048-006-0065-x" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Uhlenberg2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Uhlenberg, B., Schuelke, M., Ruschendorf, F., Ruf, N., Kaindl, A. M., Henneke, M., Thiele, H., Stoltenburg-Didinger, G., Aksu, F., Topaloglu, H., Nurnberg, P., Hubner, C., Weschke, B., Gartner, J.
|
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<strong>Mutations in the gene encoding gap junction protein alpha-12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.</strong>
|
|
Am. J. Hum. Genet. 75: 251-260, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 737 only, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15192806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15192806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15192806[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=15192806" 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/10.1086/422763" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Wolf2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wolf, N. I., Cundall, M., Rutland, P., Rosser, E., Surtees, R., Benton, S., Chong, W. K., Malcolm, S., Ebinger, F., Bitner-Glindzicz, M., Woodward, K. J.
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<strong>Frameshift mutation in GJA12 leading to nystagmus, spastic ataxia and CNS dys-/demyelination.</strong>
|
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Neurogenetics 8: 39-44, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16969684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16969684</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16969684" 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/s10048-006-0062-0" target="_blank">Full Text</a>]
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</p>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 7/1/2014
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Matthew B. Gross - updated : 2/27/2014<br>Cassandra L. Kniffin - updated : 8/13/2013<br>Cassandra L. Kniffin - updated : 10/10/2011<br>Cassandra L. Kniffin - updated : 8/10/2011<br>Cassandra L. Kniffin - updated : 7/13/2010<br>Cassandra L. Kniffin - updated : 1/6/2010<br>Cassandra L. Kniffin - updated : 1/6/2009<br>Cassandra L. Kniffin - updated : 2/28/2007<br>Anne M. Stumpf - updated : 7/16/2004
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 7/15/2004
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
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</span>
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</div>
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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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carol : 08/06/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 09/13/2022<br>carol : 12/18/2018<br>carol : 11/23/2016<br>carol : 11/15/2016<br>alopez : 08/13/2015<br>mcolton : 8/3/2015<br>carol : 9/4/2014<br>carol : 7/2/2014<br>mcolton : 7/1/2014<br>ckniffin : 7/1/2014<br>mgross : 2/27/2014<br>carol : 9/25/2013<br>carol : 8/16/2013<br>ckniffin : 8/13/2013<br>terry : 10/5/2012<br>carol : 3/12/2012<br>carol : 10/12/2011<br>terry : 10/12/2011<br>ckniffin : 10/10/2011<br>wwang : 8/16/2011<br>ckniffin : 8/10/2011<br>wwang : 7/13/2010<br>ckniffin : 7/13/2010<br>wwang : 1/21/2010<br>ckniffin : 1/6/2010<br>wwang : 1/13/2009<br>ckniffin : 1/6/2009<br>ckniffin : 11/26/2008<br>carol : 12/26/2007<br>wwang : 3/5/2007<br>ckniffin : 2/28/2007<br>carol : 5/10/2006<br>carol : 5/10/2006<br>ckniffin : 5/4/2006<br>alopez : 7/16/2004
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 608803
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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GAP JUNCTION PROTEIN, GAMMA-2; GJC2
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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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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
GAP JUNCTION PROTEIN, ALPHA 12; GJA12<br />
|
|
GAP JUNCTION PROTEIN, 47-KD<br />
|
|
CONNEXIN 47; CX47<br />
|
|
CONNEXIN 46.6; CX46.6
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: GJC2</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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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 870287007;
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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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<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: 1q42.13
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:228,149,930-228,159,826 </span>
|
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</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
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<th>
|
|
Phenotype
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
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<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
1q42.13
|
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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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?Spastic paraplegia 44, autosomal recessive
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
613206
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
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</tr>
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|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Leukodystrophy, hypomyelinating, 2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
608804
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
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</tr>
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Lymphatic malformation 3
|
|
</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
613480
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
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</tr>
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</tbody>
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</table>
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</div>
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</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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<h4>
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<span class="mim-font">
|
|
<strong>TEXT</strong>
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</span>
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</h4>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
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</h4>
|
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</div>
|
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<span class="mim-text-font">
|
|
<p>The complete coding sequence of the GJA12 (GJC2) gene has been deposited in GenBank (AF014643). The GJA12 sequence encodes a 436-amino acid protein (GenBank AAB94511).</p><p>Orthmann-Murphy et al. (2007) noted that the GJC2 gene has 2 potential ATG start codons: 1 is located in the 5-prime untranslated region and is 9 nucleotides upstream of the ATG conventionally considered to be the connexin start codon. The protein was found to be expressed on primate oligodendrocytes. </p><p>For background information on connexins, see CX26 (GJB2; 121011).</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">
|
|
<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>Gap junction proteins are members of a large family of homologous connexins and comprise 4 transmembrane, 2 extracellular, and 3 cytoplasmic domains. They have been identified in a broad range of mammalian tissues, and most tissues expressed more than 1 species of connexin protein. Menichella et al. (2003) found that Cx47 (Gja12) is expressed specifically in oligodendrocytes and that its expression is regulated in parallel with other myelin genes. Cx47 and Cx32 (Gjb1; 304040) partially colocalized in oligodendrocytes, which together with Schwann cells synthesize the multilamellar myelin membranes surrounding axons. </p><p>By RT-PCR analysis, Uhlenberg et al. (2004) examined the expression of GJA12 in comparison with that of GJB1. Both were more highly expressed in brain and spinal cord than in peripheral nerve tissue. GJA12 could be amplified from sciatic and sural nerves of healthy adults. </p><p>Uhlenberg et al. (2004) remarked that GJA12 seems to be more important for oligodendrocyte homeostasis than GJB1, which is mutant in X-linked Charcot-Marie-Tooth disease (CMTX1; 302800). </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>
|
|
<span class="mim-font">
|
|
<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">
|
|
<p>The GJA12 gene consists of a single exon (Uhlenberg et al., 2004). </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">
|
|
<strong>Mapping</strong>
|
|
</span>
|
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</h4>
|
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</div>
|
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<span class="mim-text-font">
|
|
<p>The GJA12 gene maps to chromosome 1q41-q42 (Uhlenberg et al., 2004). </p><p>Gross (2014) mapped the GJC2 gene to chromosome 1q42.13 based on an alignment of the GJC2 sequence (GenBank AF014643) 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>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
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</h4>
|
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</div>
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|
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<span class="mim-text-font">
|
|
<p><strong><em>Hypomyelinating Leukodystrophy 2</em></strong></p><p>
|
|
In a consanguineous Turkish family and 2 nonconsanguineous German families with autosomal recessive hypomyelinating leukodystrophy (HLD2; 608804), also designated PMLD1, Uhlenberg et al. (2004) identified 5 different GJA12 mutations; they could not find GJA12 mutations in 3 other affected families. As expected, patients from the consanguineous family displayed a homozygous mutation, 857T-C (608803.0001). The 2 German families showed compound heterozygous GJA12 mutations. Some patients showed reduced nerve conduction velocities, which indicated the presence of a mild peripheral demyelinating motor neuropathy, predominantly of the lower limbs, consistent with GJA12 expression in sural and sciatic nerve tissue. Since Gjb1 and Gja12 are functionally redundant in mice, Uhlenberg et al. (2004) favored the hypothesis that the missense mutants of GJA12 found in their patients with Pelizaeus-Merzbacher-like disease (PMLD) displayed toxic gain of function in oligodendrocytes. Orthmann-Murphy et al. (2007) stated that the alternative ATG start codon used by Uhlenberg et al. (2004) is unlikely to be the initiation codon. Thus, the mutations described by Uhlenberg et al. (2004) contain 3 additional amino acids. </p><p>Wolf et al. (2007) identified a homozygous deletion in the GJA12 gene (608803.0006) in 2 sibs with hypomyelinating leukodystrophy who were born of consanguineous Pakistani parents. </p><p>Henneke et al. (2008) identified 11 mutations (see, e.g., 608803.0007) in the GJA12 gene in affected members of 14 (7.7%) of 182 families with a PMLD-like phenotype. The authors concluded that GJA12 mutations are not a common cause for a PMLD-like disorder. </p><p>Diekmann et al. (2010) investigated the in vitro functional effects of 4 different PMLD-like GJC2 mutations in HeLa cells and oligodendrocyte precursors. The mutants thr265-to-ala (T265A) and a complex mutation (A98G_V99insT) were retained in the endoplasmic reticulum (ER), gly149-to-ser (G149S) localized to both the ER and the plasma membrane, and thr398-to-ile (T398I )formed gap junctional plaques at the plasma membrane. Voltage clamp studies showed significantly decreased hemichannel currents for gly236-to-arg (G236R), T265A, and A98G_V99insT. In contrast, T398I revealed hemichannel currents comparable to wildtype, but these channels were dysfunctional under depolarization activation conditions. The findings indicated that PMLD is most often caused by a loss of function, but that channel dysfunction may also occur. </p><p><strong><em>Spastic Paraplegia 44</em></strong></p><p>
|
|
In 3 affected members of an Italian family with hereditary spastic paraplegia-44 (SPG44; 613206), Orthmann-Murphy et al. (2009) identified a homozygous mutation in the GJC2 gene (I33M; 608803.0008). Heterozygous family members were unaffected. The authors noted that the phenotype was less severe than hypomyelinating leukoencephalopathy-2 (HLD2; 608804), an allelic disorder. </p><p><strong><em>Lymphatic Malformation 3</em></strong></p><p>
|
|
In affected members of 2 large families with autosomal dominant lymphatic malformation-3 (LMPHM3; 613480), Ferrell et al. (2010) identified 2 different heterozygous mutations in the GJC2 gene (608803.0009 and 608803.0010, respectively). Both mutations affected the extracellular domain. Affected individuals had onset in the first or second decade of uncomplicated lymphedema of the lower limbs, and some later developed upper limb involvement. Incomplete penetrance was observed. Ferrell et al. (2010) hypothesized that the mutations may result in impaired channel activity, which may cause impaired coordination of pulsatile lymphatic flow. Four additional putative mutations in the GJC2 gene were identified in 4 smaller families with lymphedema; no functional studies were performed. </p><p>By linkage analysis followed by whole-exome sequencing, Ostergaard et al. (2011) identified a heterozygous mutation in the GJC2 gene (S48L; 608803.0009) in 8 affected members of a family with autosomal dominant primary lymphedema. Genetic analysis of an unrelated affected family identified the same pathogenic mutation. Further sequencing of this gene in 19 unrelated individuals with lymphedema identified 3 with mutations in the GJC2 gene, 2 of whom also carried the S48L substitution. Ostergaard et al. (2011) concluded that mutations in GJC2 are a significant cause of autosomal dominant primary lymphedema. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Gja12 knockout mice are completely Gja12-deficient but clinically normal (Odermatt et al., 2003). Mice lacking both Cx47 and Cx32 (Gjb1) develop severe oligodendrocyte death and present with tremor and tonic seizures (Odermatt et al., 2003; Menichella et al., 2003). By electron microscopy, Odermatt et al. (2003) observed conspicuous vacuolation of nerve fibers in central nervous system white matter of Cx47-deficient mice, particularly at the site of the optic nerve where axons are first contacted by oligodendrocytes and myelination starts. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>13 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 LEUKODYSTROPHY, HYPOMYELINATING, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GJC2, MET286THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315311,
|
|
|
|
|
|
gnomAD: rs74315311,
|
|
|
|
|
|
ClinVar: RCV000002152, RCV002287318
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a consanguineous Turkish family, Uhlenberg et al. (2004) found that members with autosomal recessive hypomyelinating leukodystrophy (HLD2; 608804) were homozygous for a T-to-C transition at cDNA position 857 of the GJA12 gene that was predicted to result in a met286-to-thr amino acid substitution (M286T). Three affected members had seizures. Unaided walking was never achieved by 2 and, at age 5, was achieved by a third affected member. </p><p>Orthmann-Murphy et al. (2007) stated that this mutation is MET283THR (M283T), when using a different ATG initiation codon. Expression of the mutant M283T protein in HeLa cells showed that the mutant protein partially accumulated in the endoplasmic reticulum, although some was expressed at the cell membrane. Mutant protein that formed membrane puncta did not form functional gap junctions, consistent with a loss of function. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 LEUKODYSTROPHY, HYPOMYELINATING, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GJC2, PRO90SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315312,
|
|
|
|
|
|
gnomAD: rs74315312,
|
|
|
|
|
|
ClinVar: RCV000002153
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a nonconsanguineous German family, Uhlenberg et al. (2004) found that a child with autosomal recessive hypomyelinating leukodystrophy (HLD2; 608804) was compound heterozygous for a C-to-T transition at cDNA position 268 of the GJA12 gene on the paternal allele, predicted to result in a pro90-to-ser amino acid substitution (P90S), and a single-basepair deletion (989delC; 608803.0003) on the maternal allele, leading to a frameshift and a nonsense peptide of 141 amino acids after amino acid 329 (cysteine). </p><p>Orthmann-Murphy et al. (2007) stated that this mutation is PRO87SER (P87S), when using a different ATG initiation codon. Expression of the mutant P87S protein in HeLa cells showed that most of the mutant protein accumulated in the endoplasmic reticulum and failed to form functional gap junctions, consistent with a loss of function. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 LEUKODYSTROPHY, HYPOMYELINATING, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GJC2, 1-BP DEL, 989C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs796065027,
|
|
|
|
|
|
|
|
ClinVar: RCV000002154
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 1-bp deletion in the GJC2 gene (989delC) that was found in compound heterozygous state in a patient with autosomal recessive hypomyelinating leukodystrophy (HLD2; 608804) by Uhlenberg et al. (2004), see 608803.0002. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 LEUKODYSTROPHY, HYPOMYELINATING, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GJC2, ARG240TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315313,
|
|
|
|
|
|
gnomAD: rs74315313,
|
|
|
|
|
|
ClinVar: RCV000002155, RCV001723533
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a nonconsanguineous German family, Uhlenberg et al. (2004) studied a patient with autosomal recessive hypomyelinating leukodystrophy (HLD2; 608804) and found compound heterozygosity for 2 mutations in the GJC2 gene: a C-to-T transition at cDNA position 718 on the paternal allele representing a nonsense mutation (R240X), and a T-to-G transversion at cDNA position 814 on the maternal allele, leading to replacement of tyrosine by aspartic acid (Y272D; 608803.0005). </p><p>Using the ATG initiation codon cited by Orthmann-Murphy et al. (2007), this mutation would be ARG237TER (R237X). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 LEUKODYSTROPHY, HYPOMYELINATING, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GJC2, TYR272ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315314,
|
|
|
|
|
|
gnomAD: rs74315314,
|
|
|
|
|
|
ClinVar: RCV000002156
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the tyr272-to-asp (Y272D) mutation in the GJC2 gene that was found in compound heterozygous state in a patient with autosomal recessive hypomyelinating leukodystrophy (HLD2; 608804) by Uhlenberg et al. (2004), see 608803.0004. </p><p>Orthmann-Murphy et al. (2007) stated that this mutation is TYR269ASP (Y269D), when using a different ATG initiation codon. Expression of the mutant Y269D protein in HeLa cells showed that most of the mutant protein accumulated in the endoplasmic reticulum and failed to form functional gap junctions, consistent with a loss of function. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 LEUKODYSTROPHY, HYPOMYELINATING, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GJC2, 34-BP DEL, NT914
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs796065028,
|
|
|
|
|
|
|
|
ClinVar: RCV000002157, RCV001781168
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs, born of consanguineous Pakistani parents, with autosomal recessive hypomyelinating leukodystrophy (HLD2; 608804), Wolf et al. (2007) identified a homozygous 34-bp deletion in the GJA12 gene (del914-947), resulting in a frameshift and a truncated 154-residue peptide. Direct sequencing showed that the deletion was flanked by a 13-bp repeat sequence that may have contributed to formation of the deletion. The 2 sibs showed different clinical phenotypes. The older developed nystagmus at age 4 months, ataxia at 2 years, and spasticity at 6 years. The spasticity progressed, and she was wheelchair-bound by age 16 years. Her younger brother showed nystagmus at age 4 weeks as well as moderately impaired psychomotor development, and was never able to walk independently. He also had a severe sensory neuropathy, which may not have been related to the disorder. Both showed mainly dysmyelination in addition to progressive demyelination on brain MRI. </p><p>Salviati et al. (2007) reported the same homozygous 34-bp deletion (del914-947) in another affected Pakistani girl. Both unaffected parents carried the deletion and denied consanguinity. The deletion was not identified in 200 control alleles. Salviati et al. (2007) suggested a loss-of-function effect. </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>.0007 LEUKODYSTROPHY, HYPOMYELINATING, 2</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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GJC2, 1-BP INS, 695G
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<br />
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SNP: rs796065029,
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ClinVar: RCV000002158
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of 2 presumably unrelated Algerian families with hypomyelinating leukodystrophy (HLD2; 608804), Henneke et al. (2008) identified a homozygous 1-bp insertion (695insG) in the GJC2 gene, resulting in a frameshift and premature termination. </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>.0008 SPASTIC PARAPLEGIA 44 (1 family)</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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GJC2, ILE33MET
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<br />
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SNP: rs75469429,
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gnomAD: rs75469429,
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ClinVar: RCV000002159
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 affected members of an Italian family with spastic paraplegia-44 (SPG44; 613206), Orthmann-Murphy et al. (2009) identified a homozygous 99C-G transversion in the GJC2 gene, resulting in an ile33-to-met (I33M) substitution in a highly conserved region in the first transmembrane domain. The mutation was not found in 210 control alleles. In vitro functional expression assays showed that I33M-mutant protein was able to form gap junctions at apposed cell borders and was present at the cell membrane, but homotypic gap junction channels were not functional. I33M-mutant protein was also able to form heteromeric channels with wildtype Cx43 (GJA1; 121014), but the channels opened only when a large voltage difference that would not be seen under physiologic conditions was applied. Since the mutation resulted in loss of channel function, Orthmann-Murphy et al. (2009) suggested that the comparatively milder phenotype compared to HLD2 (608804) must be due to another functional mechanism. </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>.0009 LYMPHATIC MALFORMATION 3</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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GJC2, SER48LEU
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<br />
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SNP: rs267606847,
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ClinVar: RCV000002160
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In multiple affected members of a large 3-generation family with autosomal dominant hereditary lymphedema (LMPHM3; 613480), Ferrell et al. (2010) identified a heterozygous 143C-T transition in the GJC2 gene, resulting in a ser48-to-leu (S48L) substitution in a highly conserved residue in extracellular loop 1. The mutation was not found in 500 control alleles. Affected individuals had early onset, between 0 and 15 years of age, of uncomplicated lymphedema of the lower limbs, and some later developed upper limb involvement. Four individuals had recurrent skin infections. Incomplete penetrance was observed. Ferrell et al. (2010) hypothesized that the mutation may result in impaired channel activity, which may cause impaired coordination of pulsatile lymphatic flow. </p><p>Ostergaard et al. (2011) identified a heterozygous S48L mutation in affected members of 4 additional families with LMPHM3. One of the families was of Somali origin. The phenotype was similar to that observed by Ferrell et al. (2010). </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>.0010 LYMPHATIC MALFORMATION 3</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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GJC2, ARG260CYS
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<br />
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SNP: rs267606846,
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ClinVar: RCV000002161
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In multiple affected members of a large 3-generation family with autosomal dominant hereditary lymphedema (LMPHM3; 613480), Ferrell et al. (2010) identified a heterozygous 778C-T transition in the GJC2 gene, resulting in an arg260-to-cys (R260C) substitution in a highly conserved residue in extracellular loop 2. The mutation occurred in the conserved SRPTEK motif, important for connexon docking. The mutation was not found in 500 control alleles. Affected individuals had onset between 10 and 21 years of uncomplicated lymphedema of the lower limbs with upper limb involvement developing later in some. Two patients had cellulitis. Incomplete penetrance was observed. Ferrell et al. (2010) hypothesized that the mutation may result in impaired channel activity, which may cause impaired coordination of pulsatile lymphatic flow. </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>.0011 LEUKODYSTROPHY, HYPOMYELINATING, 2</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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GJC2, -167A-G
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<br />
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SNP: rs587776888,
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ClinVar: RCV000023738, RCV000633051, RCV001781305
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a Japanese female with a mild Pelizaeus-Merzbacher-like disorder (HLD2; 608804) who was previously reported by Nezu et al. (1996), Osaka et al. (2010) identified a homozygous -167A-G mutation within the proximal GJC2 promoter that segregated with the disorder. The patient's healthy, second-cousin parents were heterozygous for the mutation, which was not found in 122 normal Japanese chromosomes. The mutation is located within a critical SOX10 binding site (site D) in the syntenic mouse Gjc2 proximal promoter and diminishes the consensus of the SOX binding sequence. Functional studies on the mouse promoter indicated that the -167A-G mutation abolishes SOX10 binding to the GJC2 promoter, resulting in a dramatic attenuation of GJC2 transcription. </p><p>Combes et al. (2012) identified the -167A-G mutation in 7 patients with a disorder similar to that in the Japanese patient reported by Osaka et al. (2010). The mutation was homozygous in 5 patients from 4 unrelated families from the same area of south Tunisia and segregated with the disease in a consanguineous family with 2 affected members; it was also found in 2 unrelated patients from the Mediterranean area in compound heterozygosity with another mutation in the GJC2 gene that had been identified by Henneke et al. (2008) in patients with HLD2. The mutation was not found in 212 healthy individuals from the same geographic regions. Functional studies in COS-7 and HEK293 cells demonstrated a higher luciferase expression with the mutated promoter than with the wildtype, suggesting a possible difference in transcription factor recruitment. </p><p>Using a new reporter luciferase assay in a human glioblastoma cell line (U138), Gotoh et al. (2014) demonstrated that the -167A-G mutation reduced transcriptional activity compared to wildtype in response to SOX10 (602229). The findings suggested that the mutation disrupts SOX10 binding, resulting in a decrease in the GJC2 expression that is important for the maintenance of myelinating oligodendrocytes. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
|
|
</div>
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|
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</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 LEUKODYSTROPHY, HYPOMYELINATING, 2</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
GJC2, GLU263LYS
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<br />
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SNP: rs397514734,
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|
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|
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|
|
ClinVar: RCV000054496
|
|
|
|
|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl, born of consanguineous Sri Lankan parents, with a severe form of hypomyelinating leukodystrophy-2 (HLD2; 608804), Biancheri et al. (2013) identified a homozygous c.787G-A transition in the GJC2 gene, resulting in a glu263-to-lys (E263K) substitution at a highly conserved residue in the extracellular loop-2 domain. (Biancheri et al. (2013) cited the mutation as c.778G-A, resulting in a glu260-to-lys (E260) substitution, based on a different numbering system.) The unaffected parents were heterozygous for the mutation, which was not found in 100 control alleles or in a large control database. Structural analysis predicted that the mutation would disrupt a salt bridge network and hamper correct pore formation and assembly. At birth the patient was noted to have nystagmus, and she subsequently showed severely delayed psychomotor development. Examination at age 7 months showed axial hypotonia, absent head control, increased muscle tone in the lower limbs, and brisk tendon reflexes. Neurophysiologic studies showed abnormal brainstem auditory evoked and visual evoked potentials. Brain MRI showed diffuse hyperintensity on T2-weighted images of the cerebral and cerebellar white matter, including the middle cerebellar peduncles and almost the entire brainstem. The white matter of the cervical spinal cord was also abnormal. At age 5 years, she had not acquired any motor milestones and was severely disabled with spasticity, mental retardation, and poor speech. Funduscopy showed optic atrophy. Biancheri et al. (2013) noted that the phenotype in this patient was consistent with the connatal form of Pelizaeus-Merzbacher disease (PMD). </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 LEUKODYSTROPHY, HYPOMYELINATING, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
GJC2, -170A-G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777496,
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|
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|
|
|
|
|
ClinVar: RCV000128464, RCV001849914
|
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|
|
|
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</span>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated patients with hypomyelinating leukodystrophy-2 (HLD2; 608804), Gotoh et al. (2014) identified a homozygous c.-170A-G transition in the promoter region of the GJC2 gene at a conserved residue within the SOX10 (602229) transcription factor binding site. Parental DNA was not available, but an unaffected sib of 1 of the patients was heterozygous for the mutation, which was not found in the dbSNP (build 139) or 1000 Genomes Project databases. The patients were of Portuguese and Polish descent, respectively. In vitro functional expression in a human glioblastoma cell line (U138) showed that activation by SOX10 was significantly decreased compared to wildtype. Studies in non-glial cells did not yield as significant a difference. The findings suggested that the mutation disrupts SOX10 binding, resulting in a decrease in the GJC2 expression that is important for the maintenance of myelinating oligodendrocytes. </p>
|
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</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
|
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Biancheri, R., Rosano, C., Denegri, L., Lamantea, E., Pinto, F., Lanza, F., Severino, M., Filocamo, M.
|
|
<strong>Expanded spectrum of Pelizaeus-Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form.</strong>
|
|
Europ. J. Hum. Genet. 21: 34-39, 2013.
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[PubMed: 22669416]
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[Full Text: https://doi.org/10.1038/ejhg.2012.93]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Combes, P., Kammoun, N., Monnier, A., Gonthier-Gueret, C., Giraud, G., Bertini, E., Chahnez, T., Fakhfakh, F., Boespflug-Tanguy, O., Vaurs-Barriere, C.
|
|
<strong>Relevance of GJC2 promoter mutation in Pelizaeus-Merzbacher-like disease.</strong>
|
|
Ann. Neurol. 71: 146-148, 2012.
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[PubMed: 21246605]
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[Full Text: https://doi.org/10.1002/ana.22295]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Diekmann, S., Henneke, M., Burckhardt, B. C., Gartner, J.
|
|
<strong>Pelizaeus-Merzbacher-like disease is caused not only by a loss of connexin47 function but also by a hemichannel dysfunction.</strong>
|
|
Europ. J. Hum. Genet. 18: 985-992, 2010.
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[PubMed: 20442743]
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[Full Text: https://doi.org/10.1038/ejhg.2010.61]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Ferrell, R. E., Baty, C. J., Kimak, M. A., Karlsson, J. M., Lawrence, E. C., Franke-Snyder, M., Meriney, S. D., Feingold, E., Finegold, D. N.
|
|
<strong>GJC2 missense mutations cause human lymphedema.</strong>
|
|
Am. J. Hum. Genet. 86: 943-948, 2010.
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[PubMed: 20537300]
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[Full Text: https://doi.org/10.1016/j.ajhg.2010.04.010]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Gotoh, L., Inoue, K., Helman, G., Mora, S., Maski, K., Soul, J. S., Bloom, M., Evans, S. H., Goto, Y., Caldovic, L., Hobson, G. M., Vanderver, A.
|
|
<strong>GJC2 promoter mutations causing Pelizaeus-Merzbacher-like disease.</strong>
|
|
Molec. Genet. Metab. 111: 393-398, 2014. Note: Erratum: Molec. Genet. Metab. 119: 293 only, 2016.
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[PubMed: 24374284]
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[Full Text: https://doi.org/10.1016/j.ymgme.2013.12.001]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Gross, M. B.
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<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 2/27/2014.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Henneke, M., Combes, P., Diekmann, S., Bertini, E., Brockmann, K., Burlina, A. P., Kaiser, J., Ohlenbusch, A., Plecko, B., Rodriguez, D., Boespflug-Tanguy, O., Gartner, J.
|
|
<strong>GJA12 mutations are a rare cause of Pelizaeus-Merzbacher-like disease.</strong>
|
|
Neurology 70: 748-754, 2008.
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|
|
|
|
|
[PubMed: 18094336]
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|
|
[Full Text: https://doi.org/10.1212/01.wnl.0000284828.84464.35]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Menichella, D. M., Goodenough, D. A., Sirkowski, E., Scherer, S. S., Paul, D. L.
|
|
<strong>Connexins are critical for normal myelination in the CNS.</strong>
|
|
J. Neurosci. 23: 5963-5973, 2003.
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|
[PubMed: 12843301]
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[Full Text: https://doi.org/10.1523/JNEUROSCI.23-13-05963.2003]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Nezu, A., Kimura, S., Uehara, S., Osaka, H., Kobayashi, T., Haraguchi, M., Inoue, K., Kawanishi, C.
|
|
<strong>Pelizaeus-Merzbacher-like disease: female case report.</strong>
|
|
Brain Dev. 18: 114-118, 1996.
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|
|
[PubMed: 8733901]
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[Full Text: https://doi.org/10.1016/0387-7604(95)00078-x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Odermatt, B., Wellershaus, K., Wallraff, A., Seifert, G., Degen, J., Euwens, C., Fuss, B., Bussow, H., Schilling, K., Steinhauser, C., Willecke, K.
|
|
<strong>Connexin 47 (Cx47)-deficient mice with enhanced green fluorescent protein reporter gene reveal predominant oligodendrocytic expression of Cx47 and display vacuolized myelin in the CNS.</strong>
|
|
J. Neurosci. 23: 4549-4559, 2003.
|
|
|
|
|
|
[PubMed: 12805295]
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|
[Full Text: https://doi.org/10.1523/JNEUROSCI.23-11-04549.2003]
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</p>
|
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</li>
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Orthmann-Murphy, J. L., Enriquez, A. D., Abrams, C. K., Scherer, S. S.
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<strong>Loss-of-function GJA12/connexin 47 mutations cause Pelizaeus-Merzbacher-like disease.</strong>
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Molec. Cell. Neurosci. 34: 629-641, 2007.
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[PubMed: 17344063]
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[Full Text: https://doi.org/10.1016/j.mcn.2007.01.010]
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Orthmann-Murphy, J. L., Salsano, E., Abrams, C. K., Bizzi, A., Uziel, G., Freidin, M. M., Lamantea, E., Zeviani, M., Scherer, S. S., Pareyson, D.
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<strong>Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations.</strong>
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Brain 132: 426-438, 2009.
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[PubMed: 19056803]
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[Full Text: https://doi.org/10.1093/brain/awn328]
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Osaka, H., Hamanoue, H., Yamamoto, R., Nezu, A., Sasaki, M., Saitsu, H., Kurosawa, K., Shimbo, H., Matsumoto, N., Inoue, K.
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<strong>Disrupted SOX10 regulation of GJC2 transcription causes Pelizaeus-Merzbacher-like disease.</strong>
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Ann. Neurol. 68: 250-254, 2010.
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[PubMed: 20695017]
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[Full Text: https://doi.org/10.1002/ana.22022]
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Ostergaard, P., Simpson, M. A., Brice, G., Mansour, S., Connell, F. C., Onoufriadis, A., Child, A. H., Hwang, J., Kalidas, K., Mortimer, P. S., Trembath, R., Jeffery, S.
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<strong>Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype.</strong>
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J. Med. Genet. 48: 251-255, 2011.
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[PubMed: 21266381]
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[Full Text: https://doi.org/10.1136/jmg.2010.085563]
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Salviati, L., Trevisson, E., Baldoin, M. C., Toldo, I., Sartori, S., Calderone, M., Tenconi, R., Laverda, A. M.
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<strong>A novel deletion in the GJA12 gene causes Pelizaeus-Merzbacher-like disease.</strong>
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Neurogenetics 8: 57-60, 2007.
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[PubMed: 17031678]
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[Full Text: https://doi.org/10.1007/s10048-006-0065-x]
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Uhlenberg, B., Schuelke, M., Ruschendorf, F., Ruf, N., Kaindl, A. M., Henneke, M., Thiele, H., Stoltenburg-Didinger, G., Aksu, F., Topaloglu, H., Nurnberg, P., Hubner, C., Weschke, B., Gartner, J.
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<strong>Mutations in the gene encoding gap junction protein alpha-12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.</strong>
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Am. J. Hum. Genet. 75: 251-260, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 737 only, 2004.
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[PubMed: 15192806]
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[Full Text: https://doi.org/10.1086/422763]
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Wolf, N. I., Cundall, M., Rutland, P., Rosser, E., Surtees, R., Benton, S., Chong, W. K., Malcolm, S., Ebinger, F., Bitner-Glindzicz, M., Woodward, K. J.
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<strong>Frameshift mutation in GJA12 leading to nystagmus, spastic ataxia and CNS dys-/demyelination.</strong>
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Neurogenetics 8: 39-44, 2007.
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[PubMed: 16969684]
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[Full Text: https://doi.org/10.1007/s10048-006-0062-0]
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