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Entry
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- *614297 - CHROMOSOME 19 OPEN READING FRAME 12; C19ORF12
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- OMIM
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<p>
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<span class="h4">*614297</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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<li role="presentation">
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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="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/614297">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<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 class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000131943;t=ENST00000323670" 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=83636" 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=614297" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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<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=ENSG00000131943;t=ENST00000323670" 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_001031726,NM_001256046,NM_001256047,NM_001282929,NM_001282930,NM_001282931,NM_031448,XM_024451734,XM_024451735,XM_047439496,XM_047439497" 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_031448" 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=614297" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.proteinatlas.org/search/C19orf12" 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/7328140,13436341,14602904,39645269,110611186,114325482,193787055,365777413,365777416,544711211,544711227,544711234,1370476026,1370476028,1938430196,2217323331,2217323334,2321946834,2462568016,2462568018,2462568020,2737871996" 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/Q9NSK7" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=83636" 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=ENSG00000131943;t=ENST00000323670" 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=C19orf12" 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=C19orf12" 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+83636" 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/C19orf12" 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:83636" 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/83636" 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=chr19&hgg_gene=ENST00000323670.14&hgg_start=29698886&hgg_end=29715789&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:25443" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:25443" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/c19orf12" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=614297[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=614297[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000131943" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=C19orf12" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=C19orf12" 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=C19orf12" 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=C19orf12&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/PA134981038" 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:25443" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0023530.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1919494" 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/C19orf12#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:1919494" 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/83636/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=83636" 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-040912-59" 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=C19orf12&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> 764736001<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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614297
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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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CHROMOSOME 19 OPEN READING FRAME 12; C19ORF12
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=C19orf12" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">C19orf12</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/19/526?start=-3&limit=10&highlight=526">19q12</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:29698886-29715789&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'})">19:29,698,886-29,715,789</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
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<a href="/clinicalSynopsis/table?mimNumber=615043,614298" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
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View Clinical Synopses
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</a>
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</span>
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
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<a href="/geneMap/19/526?start=-3&limit=10&highlight=526">
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19q12
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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?Spastic paraplegia 43, 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">
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<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
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</span>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/615043"> 615043 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
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Neurodegeneration with brain iron accumulation 4
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/614298"> 614298 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</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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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/614297" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/614297" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</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="text" class="mim-anchor"></a>
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<p>By searching for genes in a region of chromosome 19 linked to neurodegeneration with brain iron accumulation (NBIA4; <a href="/entry/614298">614298</a>), followed by RT-PCR of fibroblasts and blood, <a href="#4" class="mim-tip-reference" title="Hartig, M. B., Iuso, A., Haack, T., Kmiec, T., Jurkiewicz, E., Heim, K., Roeber, S., Tarabin, V., Dusi, S., Krajewska-Walasek, M., Jozwiak, S., Hempel, M., and 13 others. <strong>Absence of an orphan mitochondrial protein, C19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.</strong> Am. J. Hum. Genet. 89: 543-550, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21981780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21981780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21981780[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.2011.09.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21981780">Hartig et al. (2011)</a> cloned 2 splice variants of C19ORF12. The transcripts differ in their first exons, and the deduced 152- and 141-amino acid proteins differ only at their N termini. Both proteins contain a central transmembrane domain. Orthologs of the long isoform were detected in chimpanzee and chicken only, but close orthologs of the short isoform were detected in diverse animal species. Endogenous or fluorescence-tagged C19ORF12 protein localized to mitochondria. <a href="#4" class="mim-tip-reference" title="Hartig, M. B., Iuso, A., Haack, T., Kmiec, T., Jurkiewicz, E., Heim, K., Roeber, S., Tarabin, V., Dusi, S., Krajewska-Walasek, M., Jozwiak, S., Hempel, M., and 13 others. <strong>Absence of an orphan mitochondrial protein, C19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.</strong> Am. J. Hum. Genet. 89: 543-550, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21981780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21981780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21981780[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.2011.09.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21981780">Hartig et al. (2011)</a> stated that C19ORF12 is ubiquitously expressed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21981780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Landoure, G., Zhu, P.-P., Lourenco, C. M., Johnson, J. O., Toro, C., Bricceno, K. V., Rinaldi, C., Melleur, K. G., Sangare, M., Diallo, O., Pierson, T. M., Ishiura, H., and 19 others. <strong>Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.</strong> Hum. Mutat. 34: 1357-1360, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23857908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23857908</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23857908[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/10.1002/humu.22378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23857908">Landoure et al. (2013)</a> found that the C19ORF12 protein had a complex intracellular localization to the mitochondria or endoplasmic reticulum (ER) when expressed in cultured COS-7 cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23857908" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#4" class="mim-tip-reference" title="Hartig, M. B., Iuso, A., Haack, T., Kmiec, T., Jurkiewicz, E., Heim, K., Roeber, S., Tarabin, V., Dusi, S., Krajewska-Walasek, M., Jozwiak, S., Hempel, M., and 13 others. <strong>Absence of an orphan mitochondrial protein, C19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.</strong> Am. J. Hum. Genet. 89: 543-550, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21981780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21981780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21981780[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.2011.09.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21981780">Hartig et al. (2011)</a> found that expression of C19ORF12 increased with differentiation in adipocytes along with genes involved in valine, leucine, and isoleucine degradation and fatty acid metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21981780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#4" class="mim-tip-reference" title="Hartig, M. B., Iuso, A., Haack, T., Kmiec, T., Jurkiewicz, E., Heim, K., Roeber, S., Tarabin, V., Dusi, S., Krajewska-Walasek, M., Jozwiak, S., Hempel, M., and 13 others. <strong>Absence of an orphan mitochondrial protein, C19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.</strong> Am. J. Hum. Genet. 89: 543-550, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21981780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21981780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21981780[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.2011.09.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21981780">Hartig et al. (2011)</a> determined that the C19ORF12 gene spans 17 kb and contains 4 exons, including 2 alternative first exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21981780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By genomic sequence analysis, <a href="#4" class="mim-tip-reference" title="Hartig, M. B., Iuso, A., Haack, T., Kmiec, T., Jurkiewicz, E., Heim, K., Roeber, S., Tarabin, V., Dusi, S., Krajewska-Walasek, M., Jozwiak, S., Hempel, M., and 13 others. <strong>Absence of an orphan mitochondrial protein, C19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.</strong> Am. J. Hum. Genet. 89: 543-550, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21981780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21981780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21981780[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.2011.09.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21981780">Hartig et al. (2011)</a> mapped the C19ORF12 gene to chromosome 19q12. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21981780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Neurodegeneration with Brain Iron Accumulation 4, Autosomal Recessive</em></strong></p><p>
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In 24 Polish patients with neurodegeneration with brain iron accumulation-4 (NBIA4; <a href="/entry/614298">614298</a>), <a href="#4" class="mim-tip-reference" title="Hartig, M. B., Iuso, A., Haack, T., Kmiec, T., Jurkiewicz, E., Heim, K., Roeber, S., Tarabin, V., Dusi, S., Krajewska-Walasek, M., Jozwiak, S., Hempel, M., and 13 others. <strong>Absence of an orphan mitochondrial protein, C19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.</strong> Am. J. Hum. Genet. 89: 543-550, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21981780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21981780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21981780[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.2011.09.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21981780">Hartig et al. (2011)</a> identified homozygous or compound heterozygous mutations in the C19ORF12 gene (see, e.g., <a href="#0001">614297.0001</a>-<a href="#0004">614297.0004</a>). Eighteen patients carried the same 11-bp deletion (c.201_214del; <a href="#0001">614297.0001</a>), and haplotype analysis indicated a founder effect. The mutation was initially found after genomewide linkage analysis of an affected family. Two unrelated patients who were compound heterozygous for 2 missense mutations (<a href="#0003">614297.0003</a> and <a href="#0004">614297.0004</a>) had a milder phenotype. One had only impairment of fine motor skills at age 19 years, and the other presented in his forties with parkinsonism and dystonia. <a href="#4" class="mim-tip-reference" title="Hartig, M. B., Iuso, A., Haack, T., Kmiec, T., Jurkiewicz, E., Heim, K., Roeber, S., Tarabin, V., Dusi, S., Krajewska-Walasek, M., Jozwiak, S., Hempel, M., and 13 others. <strong>Absence of an orphan mitochondrial protein, C19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.</strong> Am. J. Hum. Genet. 89: 543-550, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21981780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21981780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21981780[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.2011.09.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21981780">Hartig et al. (2011)</a> suggested the designation 'mitochondrial membrane protein associated neurodegeneration (MPAN)' for this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21981780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 23 of 161 individuals with NBIA, <a href="#5" class="mim-tip-reference" title="Hogarth, P., Gregory, A., Kruer, M. C., Sanford, L., Wagoner, W., Natowicz, M. R., Egel, R. T., Subramony, S. H., Goldman, J. G., Berry-Kravis, E., Foulds, N. C., Hammans, S. R., and 9 others. <strong>New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN.</strong> Neurology 80: 268-275, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23269600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23269600</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23269600[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31827e07be" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23269600">Hogarth et al. (2013)</a> identified pathogenic mutations in the C19ORF12 gene. Seventeen patients from 16 families had biallelic mutations, whereas 6 patients from 4 families had heterozygous mutations; however, the authors considered a second occult deleterious mutation likely to be present in these patients. The 11-bp deletion (<a href="#0001">614297.0001</a>) identified by <a href="#4" class="mim-tip-reference" title="Hartig, M. B., Iuso, A., Haack, T., Kmiec, T., Jurkiewicz, E., Heim, K., Roeber, S., Tarabin, V., Dusi, S., Krajewska-Walasek, M., Jozwiak, S., Hempel, M., and 13 others. <strong>Absence of an orphan mitochondrial protein, C19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.</strong> Am. J. Hum. Genet. 89: 543-550, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21981780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21981780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21981780[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.2011.09.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21981780">Hartig et al. (2011)</a> was recurrent in individuals of Eastern European origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23269600+21981780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Deschauer, M., Gaul, C., Behrmann, C., Prokisch, H., Zierz, S., Haack, T. B. <strong>C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis.</strong> J. Neurol. 259: 2434-2439, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22584950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22584950</a>] [<a href="https://doi.org/10.1007/s00415-012-6521-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22584950">Deschauer et al. (2012)</a> identified 3 different mutations in the C19ORF12 gene (<a href="#0001">614297.0001</a>; <a href="#0002">614297.0002</a>; <a href="/entry/614296#0007">614296.0007</a>) in 3 patients from 2 unrelated families with NBIA4. All mutations occurred in compound heterozygosity. The patients had onset in the first or second decades of upper and lower motor neuron signs reminiscent of juvenile-onset amyotrophic lateral sclerosis (ALS). Clinical features included pes cavus, difficulty walking, hypo- and hyperreflexia, muscle weakness and atrophy, and variable cognitive impairment with neuropsychologic abnormalities. One patient had optic atrophy. Extrapyramidal signs, such as parkinsonism, were not present. Brain MRI of all 3 patients showed T2-weighted hypointensities in the globus pallidus with some hypointensities also in the substantia nigra and cerebral peduncles, consistent with iron deposition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22584950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 19-year-old Turkish girl with NBIA4, <a href="#7" class="mim-tip-reference" title="Kasapkara, C. S., Tumer, L., Gregory, A., Ezgu, F., Inci, A., Derinkuyu, B. E., Fox, R., Rogers, C., Hayflick, S. <strong>A new NBIA patient from Turkey with homozygous C19ORF12 mutation.</strong> Acta Neurol. Belg. 119: 623-625, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30298423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30298423</a>] [<a href="https://doi.org/10.1007/s13760-018-1026-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30298423">Kasapkara et al. (2019)</a> identified a homozygous 11-bp deletion (c.171_181del) in the C19ORF12 gene. Her consanguineous parents were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30298423" 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="Gregory, A., Lotia, M., Jeong, S. Y., Fox. R., Zhen, D., Sanford, L., Hamada, J., Jahic, A., Beetz, C., Freed, A., Kurian, M. A., Cullup, T., and 13 others. <strong>Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).</strong> Molec. Genet. Genomic Med. 7: e00736, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31087512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31087512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31087512[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/10.1002/mgg3.736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31087512">Gregory et al. (2019)</a> reported 22 individuals from 19 families with homozygous or compound heterozygous mutation in the C19ORF12 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31087512" 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>Neurodegeneration with Brain Iron Accumulation 4, Autosomal Dominant</em></strong></p><p>
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In a girl with NBIA4, born of unrelated Italian parents, <a href="#11" class="mim-tip-reference" title="Monfrini, E., Melzi, V., Buongarzone, G., Franco, G., Ronchi, D., Dilena, R., Scola, E., Vizziello, P., Bordoni, A., Bresolin, N., Comi, G. P., Corti, S., Di Fonzo, A. <strong>A de novo C19orf12 heterozygous mutation in a patient with MPAN.</strong> Parkinsonism Relat. Disord. 48: 109-111, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29295770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29295770</a>] [<a href="https://doi.org/10.1016/j.parkreldis.2017.12.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29295770">Monfrini et al. (2018)</a> identified a de novo heterozygous 2-bp deletion in the C19ORF12 gene (c.265_266delAT; <a href="#0009">614297.0009</a>). Sequencing of all exons and intron-exon boundaries of other known NBIA-associated genes did not detect other pathogenic variants. Quantitative reverse-transcription PCR in lymphocytes showed that mRNA quantity in the proband was not reduced compared to that of the parents and controls, suggesting absence of degradation through nonsense-mediated decay. The authors hypothesized that the heterozygous variant is pathogenic and suggested that the mutation may have a dominant-negative effect. They also noted the possibility that the patient has a mutation in an unidentified causative gene. They further noted that 5 previous heterozygous mutations had been reported (e.g., <a href="#5" class="mim-tip-reference" title="Hogarth, P., Gregory, A., Kruer, M. C., Sanford, L., Wagoner, W., Natowicz, M. R., Egel, R. T., Subramony, S. H., Goldman, J. G., Berry-Kravis, E., Foulds, N. C., Hammans, S. R., and 9 others. <strong>New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN.</strong> Neurology 80: 268-275, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23269600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23269600</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23269600[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31827e07be" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23269600">Hogarth et al., 2013</a>), all involving exon 3, but that those authors considered that a second mutation was likely to be present. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23269600+29295770" 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="Gregory, A., Lotia, M., Jeong, S. Y., Fox. R., Zhen, D., Sanford, L., Hamada, J., Jahic, A., Beetz, C., Freed, A., Kurian, M. A., Cullup, T., and 13 others. <strong>Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).</strong> Molec. Genet. Genomic Med. 7: e00736, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31087512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31087512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31087512[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/10.1002/mgg3.736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31087512">Gregory et al. (2019)</a> identified 18 patients with MPAN (NBIA4) from 13 families who carried heterozygous mutations in the C19ORF12 gene, all in exon 3 (e.g., <a href="#0010">614297.0010</a>-<a href="#0012">614297.0012</a>). The authors proposed a mechanism to explain how MPAN can display both autosomal recessive and autosomal dominant inheritance. In autosomal recessive MPAN, a mutation resulting in premature termination of the protein occurring in the first or second exon would be predicted to undergo nonsense-mediated decay (NMD). From parental studies, partial C19ORF12 loss of function from one such allele causes no neurologic problems. Therefore, 2 such mutant alleles are required to manifest disease. The homozygous and compound heterozygous cases presented by <a href="#3" class="mim-tip-reference" title="Gregory, A., Lotia, M., Jeong, S. Y., Fox. R., Zhen, D., Sanford, L., Hamada, J., Jahic, A., Beetz, C., Freed, A., Kurian, M. A., Cullup, T., and 13 others. <strong>Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).</strong> Molec. Genet. Genomic Med. 7: e00736, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31087512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31087512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31087512[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/10.1002/mgg3.736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31087512">Gregory et al. (2019)</a> comprised a mix of frameshift mutations predicted to undergo NMD, and missense and splicing mutations throughout the gene that were predicted to result in loss of function. On the other hand, truncating mutations occurring in the final exon of a gene or near the 3-prime end of the penultimate exon typically escape NMD; all heterozygous MPAN mutations reported by <a href="#3" class="mim-tip-reference" title="Gregory, A., Lotia, M., Jeong, S. Y., Fox. R., Zhen, D., Sanford, L., Hamada, J., Jahic, A., Beetz, C., Freed, A., Kurian, M. A., Cullup, T., and 13 others. <strong>Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).</strong> Molec. Genet. Genomic Med. 7: e00736, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31087512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31087512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31087512[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/10.1002/mgg3.736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31087512">Gregory et al. (2019)</a> were frameshift or nonsense mutations in the third and final exon of C19ORF12. <a href="#3" class="mim-tip-reference" title="Gregory, A., Lotia, M., Jeong, S. Y., Fox. R., Zhen, D., Sanford, L., Hamada, J., Jahic, A., Beetz, C., Freed, A., Kurian, M. A., Cullup, T., and 13 others. <strong>Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).</strong> Molec. Genet. Genomic Med. 7: e00736, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31087512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31087512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31087512[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/10.1002/mgg3.736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31087512">Gregory et al. (2019)</a> proposed a dominant-negative mechanism for these heterozygous mutant alleles based on homomultimerization of the C19ORF12 protein. Additionally, <a href="#3" class="mim-tip-reference" title="Gregory, A., Lotia, M., Jeong, S. Y., Fox. R., Zhen, D., Sanford, L., Hamada, J., Jahic, A., Beetz, C., Freed, A., Kurian, M. A., Cullup, T., and 13 others. <strong>Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).</strong> Molec. Genet. Genomic Med. 7: e00736, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31087512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31087512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31087512[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/10.1002/mgg3.736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31087512">Gregory et al. (2019)</a> identified individuals from 5 families who carried an 11-bp deletion in exon 3 (<a href="#0001">614297.0001</a>), in homozygosity or compound heterozygosity with another pathogenic mutation. No heterozygous parent showed features of MPAN. Both this mutation and another found in a large family showing autosomal dominant inheritance (<a href="#0010">614297.0010</a>) truncate the protein at the same codon (79); the difference in the mutant proteins is the identity of the 9 terminal amino acids. <a href="#3" class="mim-tip-reference" title="Gregory, A., Lotia, M., Jeong, S. Y., Fox. R., Zhen, D., Sanford, L., Hamada, J., Jahic, A., Beetz, C., Freed, A., Kurian, M. A., Cullup, T., and 13 others. <strong>Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).</strong> Molec. Genet. Genomic Med. 7: e00736, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31087512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31087512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31087512[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/10.1002/mgg3.736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31087512">Gregory et al. (2019)</a> hypothesized that a normal sequence of residues 69-76 may be necessary and sufficient for the heterozygous mutant protein to homomultimerize with the wildtype protein from the other allele, which could damage the function of the protein complex or induce its degradation. <a href="#3" class="mim-tip-reference" title="Gregory, A., Lotia, M., Jeong, S. Y., Fox. R., Zhen, D., Sanford, L., Hamada, J., Jahic, A., Beetz, C., Freed, A., Kurian, M. A., Cullup, T., and 13 others. <strong>Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).</strong> Molec. Genet. Genomic Med. 7: e00736, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31087512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31087512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31087512[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/10.1002/mgg3.736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31087512">Gregory et al. (2019)</a> also considered haploinsufficiency as an alternate disease mechanism for heterozygous mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31087512" 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 43</em></strong></p><p>
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In 2 sisters, born of consanguineous Malian parents, originally reported by <a href="#10" class="mim-tip-reference" title="Meilleur, K. G., Traore, M., Sangare, M., Britton, A., Landoure, G., Coulibaly, S., Niare, B., Mochel, F., La Pean, A., Rafferty, I., Watts, C., Shriner, D., Littleton-Kearney, M. T., Blackstone, C., Singleton, A., Fischbeck, K. H. <strong>Hereditary spastic paraplegia and amyotrophy associated with a novel locus on chromosome 19.</strong> Neurogenetics 11: 313-318, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20039086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20039086</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20039086[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s10048-009-0230-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20039086">Meilleur et al. (2010)</a> as having autosomal recessive spastic paraplegia-43 (SPG43; <a href="/entry/615043">615043</a>), <a href="#9" class="mim-tip-reference" title="Landoure, G., Zhu, P.-P., Lourenco, C. M., Johnson, J. O., Toro, C., Bricceno, K. V., Rinaldi, C., Melleur, K. G., Sangare, M., Diallo, O., Pierson, T. M., Ishiura, H., and 19 others. <strong>Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.</strong> Hum. Mutat. 34: 1357-1360, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23857908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23857908</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23857908[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/10.1002/humu.22378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23857908">Landoure et al. (2013)</a> identified a homozygous missense mutation in the C19ORF12 gene (A63P; <a href="#0006">614297.0006</a>). The mutation was found by exome sequencing of 1 of the sisters. Sequencing of the coding region of C19ORF12 in 16 Australians, 46 French, 195 Americans, and 170 Japanese presenting with hereditary spastic paraplegia did not identify any other variants, suggesting that C19ORF12 mutation is likely a rare cause of this phenotype. <a href="#9" class="mim-tip-reference" title="Landoure, G., Zhu, P.-P., Lourenco, C. M., Johnson, J. O., Toro, C., Bricceno, K. V., Rinaldi, C., Melleur, K. G., Sangare, M., Diallo, O., Pierson, T. M., Ishiura, H., and 19 others. <strong>Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.</strong> Hum. Mutat. 34: 1357-1360, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23857908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23857908</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23857908[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/10.1002/humu.22378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23857908">Landoure et al. (2013)</a> identified the same homozygous A63P mutation in 2 sibs from a consanguineous Brazilian family with NBIA4, and haplotype analysis indicated a founder effect between the Malian and Brazilian families. <a href="#9" class="mim-tip-reference" title="Landoure, G., Zhu, P.-P., Lourenco, C. M., Johnson, J. O., Toro, C., Bricceno, K. V., Rinaldi, C., Melleur, K. G., Sangare, M., Diallo, O., Pierson, T. M., Ishiura, H., and 19 others. <strong>Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.</strong> Hum. Mutat. 34: 1357-1360, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23857908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23857908</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23857908[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/10.1002/humu.22378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23857908">Landoure et al. (2013)</a> suggested that the phenotypic differences between the 2 families may be due to other genetic or environmental factors or stochastic effects, and concluded that C19ORF12 mutations cause a neurologic disease spectrum that may or may not include brain iron deposition. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23857908+20039086" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<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> rs515726204 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs515726204;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/rs515726204?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=rs515726204" 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=rs515726204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 13 of 24 Polish probands with neurodegeneration with brain iron accumulation-4 (NBIA4; <a href="/entry/614298">614298</a>), <a href="#4" class="mim-tip-reference" title="Hartig, M. B., Iuso, A., Haack, T., Kmiec, T., Jurkiewicz, E., Heim, K., Roeber, S., Tarabin, V., Dusi, S., Krajewska-Walasek, M., Jozwiak, S., Hempel, M., and 13 others. <strong>Absence of an orphan mitochondrial protein, C19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.</strong> Am. J. Hum. Genet. 89: 543-550, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21981780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21981780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21981780[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.2011.09.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21981780">Hartig et al. (2011)</a> identified a homozygous 11-bp deletion (c.204_214del, NM_001031726.2) in the C19ORF12 gene, resulting in a frameshift and premature stop codon (Gly69ArgfsTer10) leading to a predicted truncation of more than 50% of the protein. Immunoblot analysis showed absence of the protein in patient fibroblasts, consistent with a loss of function. Haplotype analysis suggested a founder effect, with the mutation occurring at least 50 to 100 generations earlier. The mutation was not found in 750 control chromosomes. Three additional probands were compound heterozygous for the 11-bp deletion and another missense mutation in the C19ORF12 gene (see, e.g., T11M, <a href="#0002">614297.0002</a>). The mean age at onset was 9.2 years (range, 4 to 20), but most presented before age 11. The most common presenting symptom was gait or speech difficulty, followed by extrapyramidal signs, oromandibular and generalized dystonia, and parkinsonism. Most had progressive involvement of the corticospinal tract, with spasticity, hyperreflexia, and extensor plantar responses. Other features included motor axonal neuropathy, optic atrophy, and cognitive decline. Brain MRI showed hypointensities in the globus pallidus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21981780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Hogarth, P., Gregory, A., Kruer, M. C., Sanford, L., Wagoner, W., Natowicz, M. R., Egel, R. T., Subramony, S. H., Goldman, J. G., Berry-Kravis, E., Foulds, N. C., Hammans, S. R., and 9 others. <strong>New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN.</strong> Neurology 80: 268-275, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23269600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23269600</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23269600[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31827e07be" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23269600">Hogarth et al. (2013)</a> identified the homozygous 11-bp deletion in 3 unrelated patients with NBIA4 of Bosnian, Ukrainian, and mixed Eastern European ancestry, respectively. Four additional NBIA4 patients, including a pair of sibs, were compound heterozygous for the 11-bp deletion and another pathogenic C19ORF12 mutation. All of these patients were of Polish or other Eastern European ancestry. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23269600" 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>.0002 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397514477 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514477;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/rs397514477?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=rs397514477" 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=rs397514477" 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=RCV000024152 OR RCV000426086 OR RCV001004003 OR RCV003743545 OR RCV004700277 OR RCV005016294" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024152, RCV000426086, RCV001004003, RCV003743545, RCV004700277, RCV005016294" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024152...</a>
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<p>In a Polish patient with neurodegeneration with brain iron accumulation-4 (NBIA4; <a href="/entry/614298">614298</a>), <a href="#4" class="mim-tip-reference" title="Hartig, M. B., Iuso, A., Haack, T., Kmiec, T., Jurkiewicz, E., Heim, K., Roeber, S., Tarabin, V., Dusi, S., Krajewska-Walasek, M., Jozwiak, S., Hempel, M., and 13 others. <strong>Absence of an orphan mitochondrial protein, C19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.</strong> Am. J. Hum. Genet. 89: 543-550, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21981780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21981780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21981780[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.2011.09.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21981780">Hartig et al. (2011)</a> identified a homozygous c.32C-T transition (c.32C-T, NM_001031726.2) in the C19ORF12 gene, resulting in a thr11-to-met (T11M) substitution upstream of the initiation codon of the shorter isoform, thus only affecting the longer isoform. Another patient was compound heterozygous for T11M and the founder 11-bp deletion (<a href="#0001">614297.0001</a>). Neither mutation was found in 750 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21981780" 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="Dogu, O., Krebs, C. E., Kaleagasi, H., Demirtas, Z., Oksuz, N., Walker, R. H., Paisan-Ruiz, C. <strong>Rapid disease progression in adult-onset mitochondrial membrane protein-associated neurodegeneration.</strong> Clin. Genet. 84: 350-355, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23278385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23278385</a>] [<a href="https://doi.org/10.1111/cge.12079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23278385">Dogu et al. (2013)</a> identified a homozygous T11M mutation in 3 affected individuals from 2 unrelated consanguineous Turkish families with NBIA4. The mutation was found by homozygosity mapping and candidate gene sequencing. All patients had a relatively late onset of the disorder, between 25 and 29 years of age, and 2 showed very rapid progression leading to death 12 and 36 months after admission, respectively. The features were typical of the disorder, with progressive parkinsonism unresponsive to L-DOPA therapy, pyramidal signs, and tremor. Two of the 3 patients had cognitive impairment with behavioral abnormalities. <a href="#2" class="mim-tip-reference" title="Dogu, O., Krebs, C. E., Kaleagasi, H., Demirtas, Z., Oksuz, N., Walker, R. H., Paisan-Ruiz, C. <strong>Rapid disease progression in adult-onset mitochondrial membrane protein-associated neurodegeneration.</strong> Clin. Genet. 84: 350-355, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23278385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23278385</a>] [<a href="https://doi.org/10.1111/cge.12079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23278385">Dogu et al. (2013)</a> suggested that the phenotypic variation in these patients compared to previously reported NBIA4 patients may be due to the involvement of other genetic, epigenetic, or environmental factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23278385" 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 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs515726205 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs515726205;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/rs515726205?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=rs515726205" 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=rs515726205" 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=RCV000024153 OR RCV000414809 OR RCV000528859 OR RCV001781312 OR RCV003230372 OR RCV005016295" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024153, RCV000414809, RCV000528859, RCV001781312, RCV003230372, RCV005016295" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024153...</a>
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<p>In a Polish patient with neurodegeneration with brain iron accumulation-4 (NBIA4; <a href="/entry/614298">614298</a>), <a href="#4" class="mim-tip-reference" title="Hartig, M. B., Iuso, A., Haack, T., Kmiec, T., Jurkiewicz, E., Heim, K., Roeber, S., Tarabin, V., Dusi, S., Krajewska-Walasek, M., Jozwiak, S., Hempel, M., and 13 others. <strong>Absence of an orphan mitochondrial protein, C19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.</strong> Am. J. Hum. Genet. 89: 543-550, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21981780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21981780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21981780[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.2011.09.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21981780">Hartig et al. (2011)</a> identified a homozygous c.205G-A transition (c.205G-A, NM_001031726.2) in the C19ORF12 gene, resulting in a gly69-to-arg (G69R) substitution in a highly conserved residue in the transmembrane domain. Another patient was compound heterozygous for G69R and K142E (<a href="#0004">614297.0004</a>). Neither mutation was found in 750 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21981780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs146170087 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs146170087;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/rs146170087?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=rs146170087" 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=rs146170087" 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=RCV000024154 OR RCV000415210 OR RCV000509226 OR RCV000553096 OR RCV000714889 OR RCV001083182 OR RCV001844017 OR RCV001847623" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024154, RCV000415210, RCV000509226, RCV000553096, RCV000714889, RCV001083182, RCV001844017, RCV001847623" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024154...</a>
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<p>In a Polish patient with neurodegeneration with brain iron accumulation-4 (NBIA4; <a href="/entry/614298">614298</a>), <a href="#4" class="mim-tip-reference" title="Hartig, M. B., Iuso, A., Haack, T., Kmiec, T., Jurkiewicz, E., Heim, K., Roeber, S., Tarabin, V., Dusi, S., Krajewska-Walasek, M., Jozwiak, S., Hempel, M., and 13 others. <strong>Absence of an orphan mitochondrial protein, C19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.</strong> Am. J. Hum. Genet. 89: 543-550, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21981780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21981780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21981780[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.2011.09.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21981780">Hartig et al. (2011)</a> identified compound heterozygosity for 2 mutations in the C19ORF12 gene: a c.424A-G transition (c.424A-G, NM_001031726.2), resulting in a lys142-to-glu (K142E) substitution and G69R (<a href="#0003">614297.0003</a>). Neither mutation was found in 750 control chromosomes. This patient had a relatively mild form of the disorder, with only impairment of fine motor skills beginning at age 14 years. MRI performed at age 12 for a pituitary adenoma showed brain iron accumulation as an incidental finding. This same genotype (G69R and K142E) was found in 1 of 676 patients with parkinsonism. This patient presented with paranoid hallucinations at age 25 years. By age 49, he was diagnosed with Parkinson disease, with rigidity, akinesia, and mild tremor. He also had axial signs, dystonia of the legs with muscle cramps, hypophonia, hypomimia, vivid dreams, sleep disturbance, optic hallucinations, and cognitive decline. CT scan showed marked cerebral atrophy, but MRI was not performed. Both of these patients had a milder form of the disorder compared to patients with other C19ORF12 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21981780" 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> rs387907173 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907173;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/rs387907173?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=rs387907173" 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=rs387907173" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 brothers, born of consanguineous Turkish parents, with neurodegeneration with brain iron accumulation-4 (NBIA4; <a href="/entry/614298">614298</a>), <a href="#6" class="mim-tip-reference" title="Horvath, R., Holinski-Feder, E., Neeve, V. C. M., Pyle, A., Griffin, H., Ashok, D., Foley, C., Hudson, G., Rautensstrauss, B., Nurnberg, G., Nurnberg, P., Kortler, J., and 10 others. <strong>A new phenotype of brain iron accumulation with dystonia, optic atrophy, and peripheral neuropathy.</strong> Mov. Disord. 27: 789-793, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22508347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22508347</a>] [<a href="https://doi.org/10.1002/mds.24980" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22508347">Horvath et al. (2012)</a> identified a homozygous c.362T-A transversion in the C19ORF12 gene, resulting in a leu121-to-gln (L121Q) substitution in a conserved residue. Each unaffected parent was heterozygous for the mutation, which was not found in 200 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22508347" 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> rs376103979 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs376103979;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/rs376103979?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=rs376103979" 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=rs376103979" 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=RCV000074453 OR RCV000074454 OR RCV000493663 OR RCV005025116" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000074453, RCV000074454, RCV000493663, RCV005025116" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000074453...</a>
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<p>In 2 sisters, born of consanguineous Malian parents, originally reported by <a href="#10" class="mim-tip-reference" title="Meilleur, K. G., Traore, M., Sangare, M., Britton, A., Landoure, G., Coulibaly, S., Niare, B., Mochel, F., La Pean, A., Rafferty, I., Watts, C., Shriner, D., Littleton-Kearney, M. T., Blackstone, C., Singleton, A., Fischbeck, K. H. <strong>Hereditary spastic paraplegia and amyotrophy associated with a novel locus on chromosome 19.</strong> Neurogenetics 11: 313-318, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20039086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20039086</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20039086[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s10048-009-0230-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20039086">Meilleur et al. (2010)</a> as having autosomal recessive spastic paraplegia-43 (SPG43; <a href="/entry/615043">615043</a>), <a href="#9" class="mim-tip-reference" title="Landoure, G., Zhu, P.-P., Lourenco, C. M., Johnson, J. O., Toro, C., Bricceno, K. V., Rinaldi, C., Melleur, K. G., Sangare, M., Diallo, O., Pierson, T. M., Ishiura, H., and 19 others. <strong>Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.</strong> Hum. Mutat. 34: 1357-1360, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23857908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23857908</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23857908[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/10.1002/humu.22378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23857908">Landoure et al. (2013)</a> identified a homozygous c.187G-C transversion in the C19ORF12 gene, resulting in an ala63-to-pro (A63P) substitution at a highly conserved residue in the membrane domain. The mutation was found by exome sequencing of 1 of the sisters. The homozygous mutation was not found in 298 Malian controls or in 951 samples in the ClinSeq cohort. The A63P variant was present in 3 of 3,836 African American alleles in the NHLBI Exome Sequencing Project database, but not in 8,222 European American alleles in this database. Sequencing of the coding region of C19ORF12 in 16 Australians, 46 French, 195 Americans, and 170 Japanese presenting with hereditary spastic paraplegia did not identify any other variants, suggesting that C19ORF12 mutation is likely a rare cause of this phenotype. Reexamination of the older sister 5 years after the original report showed that she had severe atrophy and decreased sensation in the arms and legs and decreased reflexes, but no cognitive decline, facial or bulbar weakness, or vision loss. Brain MRI showed no abnormalities and no iron deposition. <a href="#9" class="mim-tip-reference" title="Landoure, G., Zhu, P.-P., Lourenco, C. M., Johnson, J. O., Toro, C., Bricceno, K. V., Rinaldi, C., Melleur, K. G., Sangare, M., Diallo, O., Pierson, T. M., Ishiura, H., and 19 others. <strong>Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.</strong> Hum. Mutat. 34: 1357-1360, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23857908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23857908</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23857908[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/10.1002/humu.22378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23857908">Landoure et al. (2013)</a> identified the same homozygous A63P mutation in 2 sibs from a consanguineous Brazilian family with onset of walking difficulties due to spastic paraplegia in their second decade. They had distal muscle wasting and weakness, axonal sensorimotor neuropathy, and visual loss with optic atrophy. Both became wheelchair-bound in their thirties. Brain MRI showed evidence of brain iron deposits in the globus pallidus, consistent with a diagnosis of neurodegeneration with brain iron accumulation-4 (NBIA4; <a href="/entry/614298">614298</a>). One of the sibs had memory loss and depression. Haplotype analysis indicated a founder effect between the Malian and Brazilian families. <a href="#9" class="mim-tip-reference" title="Landoure, G., Zhu, P.-P., Lourenco, C. M., Johnson, J. O., Toro, C., Bricceno, K. V., Rinaldi, C., Melleur, K. G., Sangare, M., Diallo, O., Pierson, T. M., Ishiura, H., and 19 others. <strong>Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.</strong> Hum. Mutat. 34: 1357-1360, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23857908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23857908</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23857908[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/10.1002/humu.22378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23857908">Landoure et al. (2013)</a> suggested that the phenotypic differences between the 2 families may be due to other genetic or environmental factors or stochastic effects, and concluded that C19ORF12 mutations cause a neurologic disease spectrum that may or may not include brain iron deposition. In vitro functional expression studies in COS-7 cells showed that the A63P mutant protein had a different intracellular localization compared to wildtype, with more generalized distribution throughout the cytoplasm rather than normal localization to the mitochondria or endoplasmic reticulum. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23857908+20039086" 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> rs398122409 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122409;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/rs398122409?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=rs398122409" 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=rs398122409" 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=RCV000074455 OR RCV001311507 OR RCV002265593 OR RCV004562242 OR RCV005016359" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000074455, RCV001311507, RCV002265593, RCV004562242, RCV005016359" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000074455...</a>
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<p>In 2 sibs with neurodegeneration with brain iron accumulation-4 (NBIA4; <a href="/entry/614298">614298</a>), <a href="#1" class="mim-tip-reference" title="Deschauer, M., Gaul, C., Behrmann, C., Prokisch, H., Zierz, S., Haack, T. B. <strong>C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis.</strong> J. Neurol. 259: 2434-2439, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22584950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22584950</a>] [<a href="https://doi.org/10.1007/s00415-012-6521-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22584950">Deschauer et al. (2012)</a> identified compound heterozygous mutations in the C19ORF12 gene: a 3-bp in-frame deletion (c.197_199del), resulting in the deletion of a highly conserved residue (Gly33) in the predicted transmembrane domain, and a T11M substitution (<a href="#0002">614297.0002</a>). The mother was heterozygous for the T11M mutation; DNA from the father was not available. The 3-bp deletion was not found in 1,000 control chromosomes and was absent from 80 HapMap individuals and the 1000 Genomes Project database. The patients were 27 and 17 years of age at the time of the report. Both had upper and lower motor neuron signs with pes cavus, winged scapula, and calf atrophy, and some difficulty walking. One had hyporeflexia with extensor plantar responses, whereas the other had hyperreflexia with clonus. Nerve studies showed reduced amplitudes with normal conduction times, consistent with axonal neuropathy. Both patients also had cognitive impairment with disinhibited and impulsive behavior; the younger sib had a history of global developmental delay since age 3 years. A third unrelated patient with a similar disorder was found to be compound heterozygous for the 3-bp deletion and an 11-bp deletion (<a href="#0001">614297.0001</a>). Each unaffected parent was heterozygous for 1 of the mutations. This patient had onset of gait difficulties at age 9 years, distal muscle weakness, hyperreflexia, pes cavus, atrophy of the thenar muscles, learning difficulties, visual impairment due to optic atrophy, and emotional lability. Brain MRI of all 3 patients showed T2-weighted hypointensities in the global pallidus with some hypointensities also in the substantia nigra and cerebral peduncles, consistent with iron deposition. <a href="#1" class="mim-tip-reference" title="Deschauer, M., Gaul, C., Behrmann, C., Prokisch, H., Zierz, S., Haack, T. B. <strong>C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis.</strong> J. Neurol. 259: 2434-2439, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22584950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22584950</a>] [<a href="https://doi.org/10.1007/s00415-012-6521-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22584950">Deschauer et al. (2012)</a> noted that the phenotype was reminiscent of juvenile-onset amyotrophic lateral sclerosis (ALS). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22584950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Landoure, G., Zhu, P.-P., Lourenco, C. M., Johnson, J. O., Toro, C., Bricceno, K. V., Rinaldi, C., Melleur, K. G., Sangare, M., Diallo, O., Pierson, T. M., Ishiura, H., and 19 others. <strong>Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.</strong> Hum. Mutat. 34: 1357-1360, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23857908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23857908</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23857908[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/10.1002/humu.22378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23857908">Landoure et al. (2013)</a> identified a homozygous c.197_199del in a patient with NBIA4. He presented at age 4 years with speech difficulty followed by progressive spasticity and impaired walking. Other features included psychomotor slowness, weakness and atrophy of the distal extremities, and small, pale optic discs. EMG showed denervation consistent with a motor neuropathy, and brain MRI showed iron deposition in the globus pallidus. In vitro functional expression studies in COS-7 cells showed that the mutant protein had a different intracellular localization compared to wildtype, with more generalized distribution throughout the cytoplasm rather than normal localization to the mitochondria or endoplasmic reticulum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23857908" 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> rs201987973 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs201987973;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/rs201987973?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=rs201987973" 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=rs201987973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 sisters, born of consanguineous Turkish parents, with neurodegeneration with brain iron accumulation-4 (NBIA4; <a href="/entry/614298">614298</a>), <a href="#8" class="mim-tip-reference" title="Kleffner, I., Wessling, C., Gess, B., Korsukewitz, C., Allkemper, T., Schirmacher, A., Young, P., Senderek, J., Husstedt, I. W. <strong>Behr syndrome with homozygous C19ORF12 mutation.</strong> J. Neurol. Sci. 357: 115-118, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26187298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26187298</a>] [<a href="https://doi.org/10.1016/j.jns.2015.07.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26187298">Kleffner et al. (2015)</a> identified a homozygous c.248C-T transition (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs201987973;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs201987973</a>) in the C19ORF12 gene, resulting in a pro83-to-leu (P83L) substitution at a highly conserved residue. The mutation segregated with the disorder in the family and was not found in the Exome Variant Server or 1000 Genomes Project databases, or in 96 control individuals. Functional studies of the variant and studies of patient cells were not performed, but <a href="#8" class="mim-tip-reference" title="Kleffner, I., Wessling, C., Gess, B., Korsukewitz, C., Allkemper, T., Schirmacher, A., Young, P., Senderek, J., Husstedt, I. W. <strong>Behr syndrome with homozygous C19ORF12 mutation.</strong> J. Neurol. Sci. 357: 115-118, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26187298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26187298</a>] [<a href="https://doi.org/10.1016/j.jns.2015.07.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26187298">Kleffner et al. (2015)</a> noted that the same variant had previously been identified in 2 other families with the disorder by <a href="#5" class="mim-tip-reference" title="Hogarth, P., Gregory, A., Kruer, M. C., Sanford, L., Wagoner, W., Natowicz, M. R., Egel, R. T., Subramony, S. H., Goldman, J. G., Berry-Kravis, E., Foulds, N. C., Hammans, S. R., and 9 others. <strong>New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN.</strong> Neurology 80: 268-275, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23269600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23269600</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23269600[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31827e07be" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23269600">Hogarth et al. (2013)</a>. The phenotype in the sisters included progressive optic atrophy, spastic tetraparesis, cerebellar signs, and cognitive decline, reminiscent of Behr syndrome (<a href="/entry/210000">210000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23269600+26187298" 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">rs1599534276 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1599534276;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=rs1599534276" 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=rs1599534276" 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 with neurodegeneration with brain iron accumulation-4 (NBIA4; <a href="/entry/614298">614298</a>), born of nonconsanguineous Italian parents, <a href="#11" class="mim-tip-reference" title="Monfrini, E., Melzi, V., Buongarzone, G., Franco, G., Ronchi, D., Dilena, R., Scola, E., Vizziello, P., Bordoni, A., Bresolin, N., Comi, G. P., Corti, S., Di Fonzo, A. <strong>A de novo C19orf12 heterozygous mutation in a patient with MPAN.</strong> Parkinsonism Relat. Disord. 48: 109-111, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29295770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29295770</a>] [<a href="https://doi.org/10.1016/j.parkreldis.2017.12.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29295770">Monfrini et al. (2018)</a> detected a heterozygous de novo 2-bp deletion (c.265_266delAT, NM_001031726) in exon 3 of the C19ORF12 gene that resulted in frameshift and premature termination of the protein (Met89GlyfsTer12). Sanger sequencing of other genes mutant in neurodegeneration with brain iron accumulation did not detect other pathogenic mutations or rearrangements. Quantitative RT-PCR in lymphocytes showed that mRNA quantity in the proband was not reduced compared to that of the parents and controls, suggesting absence of degradation through nonsense-mediated decay. Sequence analysis of the C19ORF12 transcripts revealed presence of the mutation in the proband and ruled out aberrant splicing. Several other tissues (hair, saliva, and urine) in addition to lymphocytes were examined and no evidence of mosaicism was seen. <a href="#11" class="mim-tip-reference" title="Monfrini, E., Melzi, V., Buongarzone, G., Franco, G., Ronchi, D., Dilena, R., Scola, E., Vizziello, P., Bordoni, A., Bresolin, N., Comi, G. P., Corti, S., Di Fonzo, A. <strong>A de novo C19orf12 heterozygous mutation in a patient with MPAN.</strong> Parkinsonism Relat. Disord. 48: 109-111, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29295770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29295770</a>] [<a href="https://doi.org/10.1016/j.parkreldis.2017.12.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29295770">Monfrini et al. (2018)</a> hypothesized that the heterozygous variant is pathogenic and suggested that the mutation may have a dominant-negative effect, although they also noted the possibility that the patient has a mutation in an unidentified causative gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29295770" 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">rs1599534394 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1599534394;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=rs1599534394" 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=rs1599534394" 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 large 3-generation family (family 18) with 9 affected individuals with neurodegeneration with brain iron accumulation-4 (NBIA4; <a href="/entry/614298">614298</a>) transmitted in an autosomal dominant pattern, <a href="#3" class="mim-tip-reference" title="Gregory, A., Lotia, M., Jeong, S. Y., Fox. R., Zhen, D., Sanford, L., Hamada, J., Jahic, A., Beetz, C., Freed, A., Kurian, M. A., Cullup, T., and 13 others. <strong>Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).</strong> Molec. Genet. Genomic Med. 7: e00736, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31087512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31087512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31087512[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/10.1002/mgg3.736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31087512">Gregory et al. (2019)</a> identified an 11-basepair deletion (c.227_237del11, NM_001031726.3) in exon 3 of the C19ORF12 gene resulting in a methionine-to-threonine substitution followed by a frameshift and premature termination codon 3 amino acids later (Met76ThrfsTer3). The mutation occurred in the third (last) exon of the C19ORF12 gene. The mutation was present in 1 individual (18-205) who was healthy at 80 years of age. Individual 18-310, an obligate carrier with an affected mother and son, appeared to have no clinical features of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31087512" 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">rs1555714808 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555714808;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=rs1555714808" 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=rs1555714808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In the proband (748-402) and her mother (748-301) from a 4-generation family (family 748) with neurodegeneration with brain iron accumulation-4 (NBIA4; <a href="/entry/614298">614298</a>), <a href="#3" class="mim-tip-reference" title="Gregory, A., Lotia, M., Jeong, S. Y., Fox. R., Zhen, D., Sanford, L., Hamada, J., Jahic, A., Beetz, C., Freed, A., Kurian, M. A., Cullup, T., and 13 others. <strong>Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).</strong> Molec. Genet. Genomic Med. 7: e00736, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31087512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31087512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31087512[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/10.1002/mgg3.736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31087512">Gregory et al. (2019)</a> detected a heterozygous c.336G-A transition (c.336G-A, NM_001031726.3) in exon 3 of the C19ORF12 gene that resulted in a trp112-to-ter (W112X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31087512" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL DOMINANT</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">rs1064797235 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1064797235;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=rs1064797235" 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=rs1064797235" 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=RCV000488270 OR RCV000502393" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000488270, RCV000502393" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000488270...</a>
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<p>In 2 adopted sibs (family 691) and an unrelated proband (family 698) with neurodegeneration with brain iron accumulation-4 (NBIA4; <a href="/entry/614298">614298</a>), <a href="#3" class="mim-tip-reference" title="Gregory, A., Lotia, M., Jeong, S. Y., Fox. R., Zhen, D., Sanford, L., Hamada, J., Jahic, A., Beetz, C., Freed, A., Kurian, M. A., Cullup, T., and 13 others. <strong>Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).</strong> Molec. Genet. Genomic Med. 7: e00736, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31087512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31087512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31087512[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/10.1002/mgg3.736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31087512">Gregory et al. (2019)</a> identified a C-to-T transition at nucleotide 238 (c.238C-T, NM_001031726.3) in exon 3 of the C19ORF12 gene resulting in a premature termination codon replacing the glutamine at codon 80 of the C19ORF12 gene (Q80X). The mutation was shown to have occurred de novo in family 698; biological parents were not available for analysis in family 691. The sibs both presented at age 10 years and shared progressive spastic tetraparesis and optic disc pallor. They differed in dysphagia and cognitive decline. The unrelated proband experienced disease onset at age 5 years with gait disturbance, optic atrophy, and neuropsychiatric symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31087512" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="Deschauer2012" class="mim-anchor"></a>
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Deschauer, M., Gaul, C., Behrmann, C., Prokisch, H., Zierz, S., Haack, T. B.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22584950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22584950</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22584950" 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/s00415-012-6521-7" target="_blank">Full Text</a>]
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Dogu, O., Krebs, C. E., Kaleagasi, H., Demirtas, Z., Oksuz, N., Walker, R. H., Paisan-Ruiz, C.
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Clin. Genet. 84: 350-355, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23278385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23278385</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23278385" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/cge.12079" target="_blank">Full Text</a>]
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<a id="Gregory2019" class="mim-anchor"></a>
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Gregory, A., Lotia, M., Jeong, S. Y., Fox. R., Zhen, D., Sanford, L., Hamada, J., Jahic, A., Beetz, C., Freed, A., Kurian, M. A., Cullup, T., and 13 others.
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<strong>Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).</strong>
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Molec. Genet. Genomic Med. 7: e00736, 2019. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31087512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31087512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31087512[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=31087512" 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/mgg3.736" target="_blank">Full Text</a>]
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<a id="Hartig2011" class="mim-anchor"></a>
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Hartig, M. B., Iuso, A., Haack, T., Kmiec, T., Jurkiewicz, E., Heim, K., Roeber, S., Tarabin, V., Dusi, S., Krajewska-Walasek, M., Jozwiak, S., Hempel, M., and 13 others.
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<strong>Absence of an orphan mitochondrial protein, C19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.</strong>
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Am. J. Hum. Genet. 89: 543-550, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21981780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21981780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21981780[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=21981780" 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.2011.09.007" target="_blank">Full Text</a>]
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Hogarth, P., Gregory, A., Kruer, M. C., Sanford, L., Wagoner, W., Natowicz, M. R., Egel, R. T., Subramony, S. H., Goldman, J. G., Berry-Kravis, E., Foulds, N. C., Hammans, S. R., and 9 others.
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<strong>New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN.</strong>
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Neurology 80: 268-275, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23269600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23269600</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23269600[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=23269600" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e31827e07be" target="_blank">Full Text</a>]
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<a id="Horvath2012" class="mim-anchor"></a>
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Horvath, R., Holinski-Feder, E., Neeve, V. C. M., Pyle, A., Griffin, H., Ashok, D., Foley, C., Hudson, G., Rautensstrauss, B., Nurnberg, G., Nurnberg, P., Kortler, J., and 10 others.
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<strong>A new phenotype of brain iron accumulation with dystonia, optic atrophy, and peripheral neuropathy.</strong>
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Mov. Disord. 27: 789-793, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22508347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22508347</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22508347" 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/mds.24980" target="_blank">Full Text</a>]
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<a id="Kasapkara2019" class="mim-anchor"></a>
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Kasapkara, C. S., Tumer, L., Gregory, A., Ezgu, F., Inci, A., Derinkuyu, B. E., Fox, R., Rogers, C., Hayflick, S.
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<strong>A new NBIA patient from Turkey with homozygous C19ORF12 mutation.</strong>
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Acta Neurol. Belg. 119: 623-625, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30298423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30298423</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30298423" 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/s13760-018-1026-5" target="_blank">Full Text</a>]
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<a id="Kleffner2015" class="mim-anchor"></a>
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Kleffner, I., Wessling, C., Gess, B., Korsukewitz, C., Allkemper, T., Schirmacher, A., Young, P., Senderek, J., Husstedt, I. W.
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<strong>Behr syndrome with homozygous C19ORF12 mutation.</strong>
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J. Neurol. Sci. 357: 115-118, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26187298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26187298</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26187298" 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.jns.2015.07.009" target="_blank">Full Text</a>]
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<a id="Landoure2013" class="mim-anchor"></a>
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Landoure, G., Zhu, P.-P., Lourenco, C. M., Johnson, J. O., Toro, C., Bricceno, K. V., Rinaldi, C., Melleur, K. G., Sangare, M., Diallo, O., Pierson, T. M., Ishiura, H., and 19 others.
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<strong>Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.</strong>
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Hum. Mutat. 34: 1357-1360, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23857908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23857908</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23857908[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=23857908" 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/humu.22378" target="_blank">Full Text</a>]
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<a id="Meilleur2010" class="mim-anchor"></a>
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Meilleur, K. G., Traore, M., Sangare, M., Britton, A., Landoure, G., Coulibaly, S., Niare, B., Mochel, F., La Pean, A., Rafferty, I., Watts, C., Shriner, D., Littleton-Kearney, M. T., Blackstone, C., Singleton, A., Fischbeck, K. H.
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<strong>Hereditary spastic paraplegia and amyotrophy associated with a novel locus on chromosome 19.</strong>
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Neurogenetics 11: 313-318, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20039086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20039086</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20039086[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=20039086" 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/s10048-009-0230-0" target="_blank">Full Text</a>]
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<a id="Monfrini2018" class="mim-anchor"></a>
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Monfrini, E., Melzi, V., Buongarzone, G., Franco, G., Ronchi, D., Dilena, R., Scola, E., Vizziello, P., Bordoni, A., Bresolin, N., Comi, G. P., Corti, S., Di Fonzo, A.
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<strong>A de novo C19orf12 heterozygous mutation in a patient with MPAN.</strong>
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Parkinsonism Relat. Disord. 48: 109-111, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29295770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29295770</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29295770" 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.parkreldis.2017.12.025" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 07/19/2019
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Sonja A. Rasmussen - updated : 06/17/2019<br>Sonja A. Rasmussen - updated : 01/10/2019<br>Cassandra L. Kniffin - updated : 5/10/2016<br>Cassandra L. Kniffin - updated : 11/12/2013<br>Cassandra L. Kniffin - updated : 11/4/2013<br>Cassandra L. Kniffin - updated : 5/23/2013<br>Cassandra L. Kniffin - updated : 5/29/2012<br>Cassandra L. Kniffin - updated : 10/20/2011
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz : 10/19/2011
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alopez : 03/08/2022
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carol : 11/21/2019<br>carol : 11/21/2019<br>carol : 11/20/2019<br>alopez : 07/19/2019<br>carol : 06/17/2019<br>carol : 01/10/2019<br>carol : 01/10/2019<br>carol : 10/20/2017<br>carol : 10/24/2016<br>joanna : 07/01/2016<br>carol : 5/11/2016<br>ckniffin : 5/10/2016<br>carol : 11/20/2013<br>ckniffin : 11/12/2013<br>carol : 11/6/2013<br>ckniffin : 11/4/2013<br>alopez : 6/12/2013<br>alopez : 6/12/2013<br>ckniffin : 5/23/2013<br>terry : 7/5/2012<br>carol : 5/31/2012<br>ckniffin : 5/29/2012<br>carol : 10/21/2011<br>ckniffin : 10/20/2011<br>mgross : 10/19/2011
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<strong>*</strong> 614297
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CHROMOSOME 19 OPEN READING FRAME 12; C19ORF12
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<strong><em>HGNC Approved Gene Symbol: C19orf12</em></strong>
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<strong>SNOMEDCT:</strong> 764736001;
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Cytogenetic location: 19q12
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:29,698,886-29,715,789 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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19q12
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?Spastic paraplegia 43, autosomal recessive
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615043
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Autosomal recessive
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3
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Neurodegeneration with brain iron accumulation 4
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<span class="mim-font">
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614298
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Autosomal dominant; Autosomal recessive
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3
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<strong>TEXT</strong>
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<strong>Cloning and Expression</strong>
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<p>By searching for genes in a region of chromosome 19 linked to neurodegeneration with brain iron accumulation (NBIA4; 614298), followed by RT-PCR of fibroblasts and blood, Hartig et al. (2011) cloned 2 splice variants of C19ORF12. The transcripts differ in their first exons, and the deduced 152- and 141-amino acid proteins differ only at their N termini. Both proteins contain a central transmembrane domain. Orthologs of the long isoform were detected in chimpanzee and chicken only, but close orthologs of the short isoform were detected in diverse animal species. Endogenous or fluorescence-tagged C19ORF12 protein localized to mitochondria. Hartig et al. (2011) stated that C19ORF12 is ubiquitously expressed. </p><p>Landoure et al. (2013) found that the C19ORF12 protein had a complex intracellular localization to the mitochondria or endoplasmic reticulum (ER) when expressed in cultured COS-7 cells. </p>
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<strong>Gene Function</strong>
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<span class="mim-text-font">
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<p>Hartig et al. (2011) found that expression of C19ORF12 increased with differentiation in adipocytes along with genes involved in valine, leucine, and isoleucine degradation and fatty acid metabolism. </p>
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<strong>Gene Structure</strong>
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<p>Hartig et al. (2011) determined that the C19ORF12 gene spans 17 kb and contains 4 exons, including 2 alternative first exons. </p>
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>By genomic sequence analysis, Hartig et al. (2011) mapped the C19ORF12 gene to chromosome 19q12. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p><strong><em>Neurodegeneration with Brain Iron Accumulation 4, Autosomal Recessive</em></strong></p><p>
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In 24 Polish patients with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Hartig et al. (2011) identified homozygous or compound heterozygous mutations in the C19ORF12 gene (see, e.g., 614297.0001-614297.0004). Eighteen patients carried the same 11-bp deletion (c.201_214del; 614297.0001), and haplotype analysis indicated a founder effect. The mutation was initially found after genomewide linkage analysis of an affected family. Two unrelated patients who were compound heterozygous for 2 missense mutations (614297.0003 and 614297.0004) had a milder phenotype. One had only impairment of fine motor skills at age 19 years, and the other presented in his forties with parkinsonism and dystonia. Hartig et al. (2011) suggested the designation 'mitochondrial membrane protein associated neurodegeneration (MPAN)' for this disorder. </p><p>In 23 of 161 individuals with NBIA, Hogarth et al. (2013) identified pathogenic mutations in the C19ORF12 gene. Seventeen patients from 16 families had biallelic mutations, whereas 6 patients from 4 families had heterozygous mutations; however, the authors considered a second occult deleterious mutation likely to be present in these patients. The 11-bp deletion (614297.0001) identified by Hartig et al. (2011) was recurrent in individuals of Eastern European origin. </p><p>Deschauer et al. (2012) identified 3 different mutations in the C19ORF12 gene (614297.0001; 614297.0002; 614296.0007) in 3 patients from 2 unrelated families with NBIA4. All mutations occurred in compound heterozygosity. The patients had onset in the first or second decades of upper and lower motor neuron signs reminiscent of juvenile-onset amyotrophic lateral sclerosis (ALS). Clinical features included pes cavus, difficulty walking, hypo- and hyperreflexia, muscle weakness and atrophy, and variable cognitive impairment with neuropsychologic abnormalities. One patient had optic atrophy. Extrapyramidal signs, such as parkinsonism, were not present. Brain MRI of all 3 patients showed T2-weighted hypointensities in the globus pallidus with some hypointensities also in the substantia nigra and cerebral peduncles, consistent with iron deposition. </p><p>In a 19-year-old Turkish girl with NBIA4, Kasapkara et al. (2019) identified a homozygous 11-bp deletion (c.171_181del) in the C19ORF12 gene. Her consanguineous parents were heterozygous for the mutation. </p><p>Gregory et al. (2019) reported 22 individuals from 19 families with homozygous or compound heterozygous mutation in the C19ORF12 gene. </p><p><strong><em>Neurodegeneration with Brain Iron Accumulation 4, Autosomal Dominant</em></strong></p><p>
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In a girl with NBIA4, born of unrelated Italian parents, Monfrini et al. (2018) identified a de novo heterozygous 2-bp deletion in the C19ORF12 gene (c.265_266delAT; 614297.0009). Sequencing of all exons and intron-exon boundaries of other known NBIA-associated genes did not detect other pathogenic variants. Quantitative reverse-transcription PCR in lymphocytes showed that mRNA quantity in the proband was not reduced compared to that of the parents and controls, suggesting absence of degradation through nonsense-mediated decay. The authors hypothesized that the heterozygous variant is pathogenic and suggested that the mutation may have a dominant-negative effect. They also noted the possibility that the patient has a mutation in an unidentified causative gene. They further noted that 5 previous heterozygous mutations had been reported (e.g., Hogarth et al., 2013), all involving exon 3, but that those authors considered that a second mutation was likely to be present. </p><p>Gregory et al. (2019) identified 18 patients with MPAN (NBIA4) from 13 families who carried heterozygous mutations in the C19ORF12 gene, all in exon 3 (e.g., 614297.0010-614297.0012). The authors proposed a mechanism to explain how MPAN can display both autosomal recessive and autosomal dominant inheritance. In autosomal recessive MPAN, a mutation resulting in premature termination of the protein occurring in the first or second exon would be predicted to undergo nonsense-mediated decay (NMD). From parental studies, partial C19ORF12 loss of function from one such allele causes no neurologic problems. Therefore, 2 such mutant alleles are required to manifest disease. The homozygous and compound heterozygous cases presented by Gregory et al. (2019) comprised a mix of frameshift mutations predicted to undergo NMD, and missense and splicing mutations throughout the gene that were predicted to result in loss of function. On the other hand, truncating mutations occurring in the final exon of a gene or near the 3-prime end of the penultimate exon typically escape NMD; all heterozygous MPAN mutations reported by Gregory et al. (2019) were frameshift or nonsense mutations in the third and final exon of C19ORF12. Gregory et al. (2019) proposed a dominant-negative mechanism for these heterozygous mutant alleles based on homomultimerization of the C19ORF12 protein. Additionally, Gregory et al. (2019) identified individuals from 5 families who carried an 11-bp deletion in exon 3 (614297.0001), in homozygosity or compound heterozygosity with another pathogenic mutation. No heterozygous parent showed features of MPAN. Both this mutation and another found in a large family showing autosomal dominant inheritance (614297.0010) truncate the protein at the same codon (79); the difference in the mutant proteins is the identity of the 9 terminal amino acids. Gregory et al. (2019) hypothesized that a normal sequence of residues 69-76 may be necessary and sufficient for the heterozygous mutant protein to homomultimerize with the wildtype protein from the other allele, which could damage the function of the protein complex or induce its degradation. Gregory et al. (2019) also considered haploinsufficiency as an alternate disease mechanism for heterozygous mutations. </p><p><strong><em>Spastic Paraplegia 43</em></strong></p><p>
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In 2 sisters, born of consanguineous Malian parents, originally reported by Meilleur et al. (2010) as having autosomal recessive spastic paraplegia-43 (SPG43; 615043), Landoure et al. (2013) identified a homozygous missense mutation in the C19ORF12 gene (A63P; 614297.0006). The mutation was found by exome sequencing of 1 of the sisters. Sequencing of the coding region of C19ORF12 in 16 Australians, 46 French, 195 Americans, and 170 Japanese presenting with hereditary spastic paraplegia did not identify any other variants, suggesting that C19ORF12 mutation is likely a rare cause of this phenotype. Landoure et al. (2013) identified the same homozygous A63P mutation in 2 sibs from a consanguineous Brazilian family with NBIA4, and haplotype analysis indicated a founder effect between the Malian and Brazilian families. Landoure et al. (2013) suggested that the phenotypic differences between the 2 families may be due to other genetic or environmental factors or stochastic effects, and concluded that C19ORF12 mutations cause a neurologic disease spectrum that may or may not include brain iron deposition. </p>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>12 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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<h4>
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<span class="mim-font">
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<strong>.0001 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL RECESSIVE</strong>
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C19ORF12, 11-BP DEL, NT204
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<br />
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SNP: rs515726204,
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gnomAD: rs515726204,
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ClinVar: RCV000024151, RCV001044832, RCV001781311, RCV003155040, RCV003904862, RCV005016293
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<p>In 13 of 24 Polish probands with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Hartig et al. (2011) identified a homozygous 11-bp deletion (c.204_214del, NM_001031726.2) in the C19ORF12 gene, resulting in a frameshift and premature stop codon (Gly69ArgfsTer10) leading to a predicted truncation of more than 50% of the protein. Immunoblot analysis showed absence of the protein in patient fibroblasts, consistent with a loss of function. Haplotype analysis suggested a founder effect, with the mutation occurring at least 50 to 100 generations earlier. The mutation was not found in 750 control chromosomes. Three additional probands were compound heterozygous for the 11-bp deletion and another missense mutation in the C19ORF12 gene (see, e.g., T11M, 614297.0002). The mean age at onset was 9.2 years (range, 4 to 20), but most presented before age 11. The most common presenting symptom was gait or speech difficulty, followed by extrapyramidal signs, oromandibular and generalized dystonia, and parkinsonism. Most had progressive involvement of the corticospinal tract, with spasticity, hyperreflexia, and extensor plantar responses. Other features included motor axonal neuropathy, optic atrophy, and cognitive decline. Brain MRI showed hypointensities in the globus pallidus. </p><p>Hogarth et al. (2013) identified the homozygous 11-bp deletion in 3 unrelated patients with NBIA4 of Bosnian, Ukrainian, and mixed Eastern European ancestry, respectively. Four additional NBIA4 patients, including a pair of sibs, were compound heterozygous for the 11-bp deletion and another pathogenic C19ORF12 mutation. All of these patients were of Polish or other Eastern European ancestry. </p>
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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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<h4>
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<span class="mim-font">
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<strong>.0002 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL RECESSIVE</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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C19ORF12, THR11MET
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<br />
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SNP: rs397514477,
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gnomAD: rs397514477,
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ClinVar: RCV000024152, RCV000426086, RCV001004003, RCV003743545, RCV004700277, RCV005016294
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a Polish patient with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Hartig et al. (2011) identified a homozygous c.32C-T transition (c.32C-T, NM_001031726.2) in the C19ORF12 gene, resulting in a thr11-to-met (T11M) substitution upstream of the initiation codon of the shorter isoform, thus only affecting the longer isoform. Another patient was compound heterozygous for T11M and the founder 11-bp deletion (614297.0001). Neither mutation was found in 750 control chromosomes. </p><p>Dogu et al. (2013) identified a homozygous T11M mutation in 3 affected individuals from 2 unrelated consanguineous Turkish families with NBIA4. The mutation was found by homozygosity mapping and candidate gene sequencing. All patients had a relatively late onset of the disorder, between 25 and 29 years of age, and 2 showed very rapid progression leading to death 12 and 36 months after admission, respectively. The features were typical of the disorder, with progressive parkinsonism unresponsive to L-DOPA therapy, pyramidal signs, and tremor. Two of the 3 patients had cognitive impairment with behavioral abnormalities. Dogu et al. (2013) suggested that the phenotypic variation in these patients compared to previously reported NBIA4 patients may be due to the involvement of other genetic, epigenetic, or environmental factors. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL RECESSIVE</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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C19ORF12, GLY69ARG
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<br />
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SNP: rs515726205,
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gnomAD: rs515726205,
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ClinVar: RCV000024153, RCV000414809, RCV000528859, RCV001781312, RCV003230372, RCV005016295
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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 a Polish patient with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Hartig et al. (2011) identified a homozygous c.205G-A transition (c.205G-A, NM_001031726.2) in the C19ORF12 gene, resulting in a gly69-to-arg (G69R) substitution in a highly conserved residue in the transmembrane domain. Another patient was compound heterozygous for G69R and K142E (614297.0004). Neither mutation was found in 750 control chromosomes. </p>
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</span>
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<br />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL RECESSIVE</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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C19ORF12, LYS142GLU
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<br />
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SNP: rs146170087,
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gnomAD: rs146170087,
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ClinVar: RCV000024154, RCV000415210, RCV000509226, RCV000553096, RCV000714889, RCV001083182, RCV001844017, RCV001847623
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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 a Polish patient with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Hartig et al. (2011) identified compound heterozygosity for 2 mutations in the C19ORF12 gene: a c.424A-G transition (c.424A-G, NM_001031726.2), resulting in a lys142-to-glu (K142E) substitution and G69R (614297.0003). Neither mutation was found in 750 control chromosomes. This patient had a relatively mild form of the disorder, with only impairment of fine motor skills beginning at age 14 years. MRI performed at age 12 for a pituitary adenoma showed brain iron accumulation as an incidental finding. This same genotype (G69R and K142E) was found in 1 of 676 patients with parkinsonism. This patient presented with paranoid hallucinations at age 25 years. By age 49, he was diagnosed with Parkinson disease, with rigidity, akinesia, and mild tremor. He also had axial signs, dystonia of the legs with muscle cramps, hypophonia, hypomimia, vivid dreams, sleep disturbance, optic hallucinations, and cognitive decline. CT scan showed marked cerebral atrophy, but MRI was not performed. Both of these patients had a milder form of the disorder compared to patients with other C19ORF12 mutations. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0005 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL RECESSIVE</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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C19ORF12, LEU121GLN
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<br />
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SNP: rs387907173,
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gnomAD: rs387907173,
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ClinVar: RCV000024323
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 brothers, born of consanguineous Turkish parents, with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Horvath et al. (2012) identified a homozygous c.362T-A transversion in the C19ORF12 gene, resulting in a leu121-to-gln (L121Q) substitution in a conserved residue. Each unaffected parent was heterozygous for the mutation, which was not found in 200 control chromosomes. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0006 SPASTIC PARAPLEGIA 43, AUTOSOMAL RECESSIVE (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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NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL RECESSIVE, INCLUDED
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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C19ORF12, ALA63PRO
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<br />
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SNP: rs376103979,
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gnomAD: rs376103979,
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ClinVar: RCV000074453, RCV000074454, RCV000493663, RCV005025116
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sisters, born of consanguineous Malian parents, originally reported by Meilleur et al. (2010) as having autosomal recessive spastic paraplegia-43 (SPG43; 615043), Landoure et al. (2013) identified a homozygous c.187G-C transversion in the C19ORF12 gene, resulting in an ala63-to-pro (A63P) substitution at a highly conserved residue in the membrane domain. The mutation was found by exome sequencing of 1 of the sisters. The homozygous mutation was not found in 298 Malian controls or in 951 samples in the ClinSeq cohort. The A63P variant was present in 3 of 3,836 African American alleles in the NHLBI Exome Sequencing Project database, but not in 8,222 European American alleles in this database. Sequencing of the coding region of C19ORF12 in 16 Australians, 46 French, 195 Americans, and 170 Japanese presenting with hereditary spastic paraplegia did not identify any other variants, suggesting that C19ORF12 mutation is likely a rare cause of this phenotype. Reexamination of the older sister 5 years after the original report showed that she had severe atrophy and decreased sensation in the arms and legs and decreased reflexes, but no cognitive decline, facial or bulbar weakness, or vision loss. Brain MRI showed no abnormalities and no iron deposition. Landoure et al. (2013) identified the same homozygous A63P mutation in 2 sibs from a consanguineous Brazilian family with onset of walking difficulties due to spastic paraplegia in their second decade. They had distal muscle wasting and weakness, axonal sensorimotor neuropathy, and visual loss with optic atrophy. Both became wheelchair-bound in their thirties. Brain MRI showed evidence of brain iron deposits in the globus pallidus, consistent with a diagnosis of neurodegeneration with brain iron accumulation-4 (NBIA4; 614298). One of the sibs had memory loss and depression. Haplotype analysis indicated a founder effect between the Malian and Brazilian families. Landoure et al. (2013) suggested that the phenotypic differences between the 2 families may be due to other genetic or environmental factors or stochastic effects, and concluded that C19ORF12 mutations cause a neurologic disease spectrum that may or may not include brain iron deposition. In vitro functional expression studies in COS-7 cells showed that the A63P mutant protein had a different intracellular localization compared to wildtype, with more generalized distribution throughout the cytoplasm rather than normal localization to the mitochondria or endoplasmic reticulum. </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>.0007 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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C19ORF12, 3-BP DEL, NT197
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<br />
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SNP: rs398122409,
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gnomAD: rs398122409,
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ClinVar: RCV000074455, RCV001311507, RCV002265593, RCV004562242, RCV005016359
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sibs with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Deschauer et al. (2012) identified compound heterozygous mutations in the C19ORF12 gene: a 3-bp in-frame deletion (c.197_199del), resulting in the deletion of a highly conserved residue (Gly33) in the predicted transmembrane domain, and a T11M substitution (614297.0002). The mother was heterozygous for the T11M mutation; DNA from the father was not available. The 3-bp deletion was not found in 1,000 control chromosomes and was absent from 80 HapMap individuals and the 1000 Genomes Project database. The patients were 27 and 17 years of age at the time of the report. Both had upper and lower motor neuron signs with pes cavus, winged scapula, and calf atrophy, and some difficulty walking. One had hyporeflexia with extensor plantar responses, whereas the other had hyperreflexia with clonus. Nerve studies showed reduced amplitudes with normal conduction times, consistent with axonal neuropathy. Both patients also had cognitive impairment with disinhibited and impulsive behavior; the younger sib had a history of global developmental delay since age 3 years. A third unrelated patient with a similar disorder was found to be compound heterozygous for the 3-bp deletion and an 11-bp deletion (614297.0001). Each unaffected parent was heterozygous for 1 of the mutations. This patient had onset of gait difficulties at age 9 years, distal muscle weakness, hyperreflexia, pes cavus, atrophy of the thenar muscles, learning difficulties, visual impairment due to optic atrophy, and emotional lability. Brain MRI of all 3 patients showed T2-weighted hypointensities in the global pallidus with some hypointensities also in the substantia nigra and cerebral peduncles, consistent with iron deposition. Deschauer et al. (2012) noted that the phenotype was reminiscent of juvenile-onset amyotrophic lateral sclerosis (ALS). </p><p>Landoure et al. (2013) identified a homozygous c.197_199del in a patient with NBIA4. He presented at age 4 years with speech difficulty followed by progressive spasticity and impaired walking. Other features included psychomotor slowness, weakness and atrophy of the distal extremities, and small, pale optic discs. EMG showed denervation consistent with a motor neuropathy, and brain MRI showed iron deposition in the globus pallidus. In vitro functional expression studies in COS-7 cells showed that the mutant protein had a different intracellular localization compared to wildtype, with more generalized distribution throughout the cytoplasm rather than normal localization to the mitochondria or endoplasmic reticulum. </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>.0008 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL RECESSIVE</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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C19ORF12, PRO83LEU ({dbSNP rs201987973})
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<br />
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SNP: rs201987973,
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gnomAD: rs201987973,
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ClinVar: RCV000211114
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In 2 sisters, born of consanguineous Turkish parents, with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Kleffner et al. (2015) identified a homozygous c.248C-T transition (rs201987973) in the C19ORF12 gene, resulting in a pro83-to-leu (P83L) substitution at a highly conserved residue. The mutation segregated with the disorder in the family and was not found in the Exome Variant Server or 1000 Genomes Project databases, or in 96 control individuals. Functional studies of the variant and studies of patient cells were not performed, but Kleffner et al. (2015) noted that the same variant had previously been identified in 2 other families with the disorder by Hogarth et al. (2013). The phenotype in the sisters included progressive optic atrophy, spastic tetraparesis, cerebellar signs, and cognitive decline, reminiscent of Behr syndrome (210000). </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 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL DOMINANT</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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C19ORF12, 2-BP DEL, 265AT
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<br />
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SNP: rs1599534276,
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ClinVar: RCV000788048
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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 a girl with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), born of nonconsanguineous Italian parents, Monfrini et al. (2018) detected a heterozygous de novo 2-bp deletion (c.265_266delAT, NM_001031726) in exon 3 of the C19ORF12 gene that resulted in frameshift and premature termination of the protein (Met89GlyfsTer12). Sanger sequencing of other genes mutant in neurodegeneration with brain iron accumulation did not detect other pathogenic mutations or rearrangements. Quantitative RT-PCR in lymphocytes showed that mRNA quantity in the proband was not reduced compared to that of the parents and controls, suggesting absence of degradation through nonsense-mediated decay. Sequence analysis of the C19ORF12 transcripts revealed presence of the mutation in the proband and ruled out aberrant splicing. Several other tissues (hair, saliva, and urine) in addition to lymphocytes were examined and no evidence of mosaicism was seen. Monfrini et al. (2018) hypothesized that the heterozygous variant is pathogenic and suggested that the mutation may have a dominant-negative effect, although they also noted the possibility that the patient has a mutation in an unidentified causative gene. </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 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL DOMINANT</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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C19ORF12, 11-BP DEL, NT227
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<br />
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SNP: rs1599534394,
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ClinVar: RCV000788049
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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 a large 3-generation family (family 18) with 9 affected individuals with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298) transmitted in an autosomal dominant pattern, Gregory et al. (2019) identified an 11-basepair deletion (c.227_237del11, NM_001031726.3) in exon 3 of the C19ORF12 gene resulting in a methionine-to-threonine substitution followed by a frameshift and premature termination codon 3 amino acids later (Met76ThrfsTer3). The mutation occurred in the third (last) exon of the C19ORF12 gene. The mutation was present in 1 individual (18-205) who was healthy at 80 years of age. Individual 18-310, an obligate carrier with an affected mother and son, appeared to have no clinical features of the disorder. </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 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL DOMINANT</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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C19ORF12, TRP112TER
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<br />
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SNP: rs1555714808,
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ClinVar: RCV000504170, RCV004023363
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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 the proband (748-402) and her mother (748-301) from a 4-generation family (family 748) with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Gregory et al. (2019) detected a heterozygous c.336G-A transition (c.336G-A, NM_001031726.3) in exon 3 of the C19ORF12 gene that resulted in a trp112-to-ter (W112X) substitution. </p>
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<strong>.0012 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL DOMINANT</strong>
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C19ORF12, GLN80TER
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SNP: rs1064797235,
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ClinVar: RCV000488270, RCV000502393
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<p>In 2 adopted sibs (family 691) and an unrelated proband (family 698) with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Gregory et al. (2019) identified a C-to-T transition at nucleotide 238 (c.238C-T, NM_001031726.3) in exon 3 of the C19ORF12 gene resulting in a premature termination codon replacing the glutamine at codon 80 of the C19ORF12 gene (Q80X). The mutation was shown to have occurred de novo in family 698; biological parents were not available for analysis in family 691. The sibs both presented at age 10 years and shared progressive spastic tetraparesis and optic disc pallor. They differed in dysphagia and cognitive decline. The unrelated proband experienced disease onset at age 5 years with gait disturbance, optic atrophy, and neuropsychiatric symptoms. </p>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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Deschauer, M., Gaul, C., Behrmann, C., Prokisch, H., Zierz, S., Haack, T. B.
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<strong>C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis.</strong>
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J. Neurol. 259: 2434-2439, 2012.
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[PubMed: 22584950]
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[Full Text: https://doi.org/10.1007/s00415-012-6521-7]
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Dogu, O., Krebs, C. E., Kaleagasi, H., Demirtas, Z., Oksuz, N., Walker, R. H., Paisan-Ruiz, C.
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<strong>Rapid disease progression in adult-onset mitochondrial membrane protein-associated neurodegeneration.</strong>
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Clin. Genet. 84: 350-355, 2013.
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[PubMed: 23278385]
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[Full Text: https://doi.org/10.1111/cge.12079]
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Gregory, A., Lotia, M., Jeong, S. Y., Fox. R., Zhen, D., Sanford, L., Hamada, J., Jahic, A., Beetz, C., Freed, A., Kurian, M. A., Cullup, T., and 13 others.
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<strong>Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).</strong>
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Molec. Genet. Genomic Med. 7: e00736, 2019. Note: Electronic Article.
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[PubMed: 31087512]
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[Full Text: https://doi.org/10.1002/mgg3.736]
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Hartig, M. B., Iuso, A., Haack, T., Kmiec, T., Jurkiewicz, E., Heim, K., Roeber, S., Tarabin, V., Dusi, S., Krajewska-Walasek, M., Jozwiak, S., Hempel, M., and 13 others.
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<strong>Absence of an orphan mitochondrial protein, C19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.</strong>
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Am. J. Hum. Genet. 89: 543-550, 2011.
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[PubMed: 21981780]
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[Full Text: https://doi.org/10.1016/j.ajhg.2011.09.007]
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Hogarth, P., Gregory, A., Kruer, M. C., Sanford, L., Wagoner, W., Natowicz, M. R., Egel, R. T., Subramony, S. H., Goldman, J. G., Berry-Kravis, E., Foulds, N. C., Hammans, S. R., and 9 others.
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<strong>New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN.</strong>
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Neurology 80: 268-275, 2013.
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[PubMed: 23269600]
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[Full Text: https://doi.org/10.1212/WNL.0b013e31827e07be]
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Horvath, R., Holinski-Feder, E., Neeve, V. C. M., Pyle, A., Griffin, H., Ashok, D., Foley, C., Hudson, G., Rautensstrauss, B., Nurnberg, G., Nurnberg, P., Kortler, J., and 10 others.
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<strong>A new phenotype of brain iron accumulation with dystonia, optic atrophy, and peripheral neuropathy.</strong>
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Mov. Disord. 27: 789-793, 2012.
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[PubMed: 22508347]
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[Full Text: https://doi.org/10.1002/mds.24980]
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Kasapkara, C. S., Tumer, L., Gregory, A., Ezgu, F., Inci, A., Derinkuyu, B. E., Fox, R., Rogers, C., Hayflick, S.
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<strong>A new NBIA patient from Turkey with homozygous C19ORF12 mutation.</strong>
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Acta Neurol. Belg. 119: 623-625, 2019.
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[PubMed: 30298423]
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[Full Text: https://doi.org/10.1007/s13760-018-1026-5]
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Kleffner, I., Wessling, C., Gess, B., Korsukewitz, C., Allkemper, T., Schirmacher, A., Young, P., Senderek, J., Husstedt, I. W.
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<strong>Behr syndrome with homozygous C19ORF12 mutation.</strong>
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J. Neurol. Sci. 357: 115-118, 2015.
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[PubMed: 26187298]
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[Full Text: https://doi.org/10.1016/j.jns.2015.07.009]
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Landoure, G., Zhu, P.-P., Lourenco, C. M., Johnson, J. O., Toro, C., Bricceno, K. V., Rinaldi, C., Melleur, K. G., Sangare, M., Diallo, O., Pierson, T. M., Ishiura, H., and 19 others.
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<strong>Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.</strong>
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Hum. Mutat. 34: 1357-1360, 2013.
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[PubMed: 23857908]
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[Full Text: https://doi.org/10.1002/humu.22378]
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Meilleur, K. G., Traore, M., Sangare, M., Britton, A., Landoure, G., Coulibaly, S., Niare, B., Mochel, F., La Pean, A., Rafferty, I., Watts, C., Shriner, D., Littleton-Kearney, M. T., Blackstone, C., Singleton, A., Fischbeck, K. H.
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<strong>Hereditary spastic paraplegia and amyotrophy associated with a novel locus on chromosome 19.</strong>
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Neurogenetics 11: 313-318, 2010.
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[PubMed: 20039086]
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[Full Text: https://doi.org/10.1007/s10048-009-0230-0]
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Monfrini, E., Melzi, V., Buongarzone, G., Franco, G., Ronchi, D., Dilena, R., Scola, E., Vizziello, P., Bordoni, A., Bresolin, N., Comi, G. P., Corti, S., Di Fonzo, A.
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<strong>A de novo C19orf12 heterozygous mutation in a patient with MPAN.</strong>
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Parkinsonism Relat. Disord. 48: 109-111, 2018.
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[PubMed: 29295770]
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[Full Text: https://doi.org/10.1016/j.parkreldis.2017.12.025]
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Ada Hamosh - updated : 07/19/2019<br>Sonja A. Rasmussen - updated : 06/17/2019<br>Sonja A. Rasmussen - updated : 01/10/2019<br>Cassandra L. Kniffin - updated : 5/10/2016<br>Cassandra L. Kniffin - updated : 11/12/2013<br>Cassandra L. Kniffin - updated : 11/4/2013<br>Cassandra L. Kniffin - updated : 5/23/2013<br>Cassandra L. Kniffin - updated : 5/29/2012<br>Cassandra L. Kniffin - updated : 10/20/2011
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