3355 lines
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Entry
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- *613277 - TRANSMEMBRANE PROTEIN 216; TMEM216
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- OMIM
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<p>
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<span class="h4">*613277</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#evolution">Evolution</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/613277">Table View</a>
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div id="mimFloatingLinksMenu">
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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>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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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=ENSG00000187049;t=ENST00000515837" 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=51259" 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=613277" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000187049;t=ENST00000515837" 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_001173990,NM_001173991,NM_001330285,NM_016499" 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_001173990" 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=613277" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=14439&isoform_id=14439_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/TMEM216" 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/7106878,15029612,48146449,115387120,119594350,221044680,291219932,291219934,380865448,972988090,1057503154" 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/Q9P0N5" 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=51259" 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=ENSG00000187049;t=ENST00000515837" 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=TMEM216" 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=TMEM216" 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+51259" 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/TMEM216" 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:51259" 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/51259" 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=chr11&hgg_gene=ENST00000515837.7&hgg_start=61392587&hgg_end=61398846&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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:25018" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=613277[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=613277[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/TMEM216/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000187049" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.gwascentral.org/search?q=TMEM216" 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=TMEM216" 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=TMEM216&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/PA162406553" 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:25018" 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/FBgn0037614.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:1920020" 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/TMEM216#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:1920020" 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/51259/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=51259" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00194710;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-100818-1" 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=TMEM216&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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</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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613277
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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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TRANSMEMBRANE PROTEIN 216; TMEM216
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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=TMEM216" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TMEM216</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/11/455?start=-3&limit=10&highlight=455">11q12.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:61392587-61398846&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'})">11:61,392,587-61,398,846</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=608091,603194,620996" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
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="3">
|
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<span class="mim-font">
|
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<a href="/geneMap/11/455?start=-3&limit=10&highlight=455">
|
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11q12.2
|
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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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Joubert syndrome 2
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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/608091"> 608091 </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">
|
|
Meckel syndrome 2
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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/603194"> 603194 </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">
|
|
Retinitis pigmentosa 98
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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/620996"> 620996 </a>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="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>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/613277" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/613277" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
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<p>TMEM216 is required for the assembly and function of cilia (<a href="#2" class="mim-tip-reference" title="Lee, J. H., Silhavy, J. L., Lee, J. E., Al-Gazali, L., Thomas, S., Davis, E. E., Bielas, S. L., Hill, K. J., Iannicelli, M., Brancati, F., Gabriel, S. B., Russ, C., and 18 others. <strong>Evolutionarily assembled cis-regulatory module at a human ciliopathy locus.</strong> Science 335: 966-969, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22282472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22282472</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22282472[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1213506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22282472">Lee et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22282472" 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 searching for genes in a region of chromosome 11 linked to Joubert syndrome-2 (JBTS2; <a href="/entry/608091">608091</a>), <a href="#1" class="mim-tip-reference" title="Edvardson, S., Shaag, A., Zenvirt, S., Erlich, Y., Hannon, G. J., Shanske, A. L., Gomori, J. M., Ekstein, J., Elpeleg, O. <strong>Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation.</strong> Am. J. Hum. Genet. 86: 93-97, 2010. Note: Erratum: 86: 294 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20036350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20036350</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20036350[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.2009.12.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20036350">Edvardson et al. (2010)</a> identified TMEM216. The deduced 87-amino acid protein has 2 transmembrane domains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20036350" 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="#4" class="mim-tip-reference" title="Valente, E. M., Logan, C. V., Mougou-Zerelli, S., Lee, J. H., Silhavy, J. L., Brancati, F., Iannicelli, M., Travaglini, L., Romani, S., Illi, B., Adams, M., Szymanska, K., and 39 others. <strong>Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. (Letter)</strong> Nature Genet. 42: 619-625, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20512146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20512146</a>] [<a href="https://doi.org/10.1038/ng.594" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20512146">Valente et al. (2010)</a> identified a 1.4-kb TMEM216 mRNA in fetal tissue. Screening of a human fetal brain cDNA library identified 4 major splice isoforms, the longest and most prevalent predicting a 148-amino acid full-length protein with 4 transmembrane domains. There was also extensive alternative splicing, resulting in transcripts encoding 3 very short proteins of 25, 30, 34 amino acids, respectively. In situ hybridization of human embryonic tissues showed TMEM216 expression in the central nervous system, limb bud, kidney, and cartilage. Specific localization was also found in mouse inner medullary collecting duct cells, human retinal pigment epithelium, and proximal renal tubule, and TMEM216 localized to the base of the primary cilium or adjacent basal body. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20512146" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using expression profiling, <a href="#2" class="mim-tip-reference" title="Lee, J. H., Silhavy, J. L., Lee, J. E., Al-Gazali, L., Thomas, S., Davis, E. E., Bielas, S. L., Hill, K. J., Iannicelli, M., Brancati, F., Gabriel, S. B., Russ, C., and 18 others. <strong>Evolutionarily assembled cis-regulatory module at a human ciliopathy locus.</strong> Science 335: 966-969, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22282472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22282472</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22282472[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1213506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22282472">Lee et al. (2012)</a> showed that TMEM216 was expressed in all tissues examined. In situ hybridization of human embryos at 4 to 8 weeks' gestation revealed ubiquitous TMEM216 expression that increased with time. TMEM216 expression appeared to parallel that of TMEM138, which is closely linked to TMEM216, in all tissues examined. Immunohistochemical analysis of mouse IMCD3 cells and transfected COS-7 cells revealed that Tmem216 localized to basal body and to the Golgi apparatus surrounding the base of cilium and that Tmem138 localized to ciliary axoneme/basal body. The 2 proteins also appeared to localize to different vesicle pools that moved toward the primary cilia over time. Tmem138 vesicles, but not Tmem216 vesicles, colocalized with endogenous Cep290 (<a href="/entry/610142">610142</a>) in IMCD3 cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22282472" 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="Malka, S., Biswas, P., Berry, A. M., Sangermano, R., Ullah, M., Lin, S., D'Antonio, M., Jestin, A., Jiao, X., Quinodoz, M., Sullivan, L., Gardner, J. C., and 34 others. <strong>Substitution of a single non-coding nucleotide upstream of TMEM216 causes non-syndromic retinitis pigmentosa and is associated with reduced TMEM216 expression.</strong> Am. J. Hum. Genet. 111: 2012-2030, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39191256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39191256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=39191256[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.2024.07.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="39191256">Malka et al. (2024)</a> analyzed expression of TMEM216 in human tissues in the GTEx database and observed significantly higher levels of TMEM216 transcript in the peripheral retina compared to levels recorded from other tissues in the GTEx database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39191256" 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="#1" class="mim-tip-reference" title="Edvardson, S., Shaag, A., Zenvirt, S., Erlich, Y., Hannon, G. J., Shanske, A. L., Gomori, J. M., Ekstein, J., Elpeleg, O. <strong>Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation.</strong> Am. J. Hum. Genet. 86: 93-97, 2010. Note: Erratum: 86: 294 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20036350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20036350</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20036350[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.2009.12.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20036350">Edvardson et al. (2010)</a> determined that the TMEM216 gene contains 3 coding exons. <a href="#4" class="mim-tip-reference" title="Valente, E. M., Logan, C. V., Mougou-Zerelli, S., Lee, J. H., Silhavy, J. L., Brancati, F., Iannicelli, M., Travaglini, L., Romani, S., Illi, B., Adams, M., Szymanska, K., and 39 others. <strong>Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. (Letter)</strong> Nature Genet. 42: 619-625, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20512146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20512146</a>] [<a href="https://doi.org/10.1038/ng.594" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20512146">Valente et al. (2010)</a> determined that the TMEM216 gene contains 6 exons with alternative splicing of exon 2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20512146+20036350" 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="Lee, J. H., Silhavy, J. L., Lee, J. E., Al-Gazali, L., Thomas, S., Davis, E. E., Bielas, S. L., Hill, K. J., Iannicelli, M., Brancati, F., Gabriel, S. B., Russ, C., and 18 others. <strong>Evolutionarily assembled cis-regulatory module at a human ciliopathy locus.</strong> Science 335: 966-969, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22282472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22282472</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22282472[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1213506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22282472">Lee et al. (2012)</a> determined that the TMEM216 gene contains 5 exons. The 23-kb intergenic region between TMEM138 and TMEM216 contains a functional conserved RFX4 (<a href="/entry/603958">603958</a>)-binding site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22282472" 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="#1" class="mim-tip-reference" title="Edvardson, S., Shaag, A., Zenvirt, S., Erlich, Y., Hannon, G. J., Shanske, A. L., Gomori, J. M., Ekstein, J., Elpeleg, O. <strong>Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation.</strong> Am. J. Hum. Genet. 86: 93-97, 2010. Note: Erratum: 86: 294 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20036350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20036350</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20036350[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.2009.12.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20036350">Edvardson et al. (2010)</a> mapped the TMEM216 gene to chromosome 11q13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20036350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By genomic sequence analysis, <a href="#2" class="mim-tip-reference" title="Lee, J. H., Silhavy, J. L., Lee, J. E., Al-Gazali, L., Thomas, S., Davis, E. E., Bielas, S. L., Hill, K. J., Iannicelli, M., Brancati, F., Gabriel, S. B., Russ, C., and 18 others. <strong>Evolutionarily assembled cis-regulatory module at a human ciliopathy locus.</strong> Science 335: 966-969, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22282472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22282472</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22282472[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1213506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22282472">Lee et al. (2012)</a> mapped the TMEM216 gene to chromosome 11q12.2, 23 kb from the TMEM138 gene. TMEM216 and TMEM138 are in a head-to-tail orientation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22282472" 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="Lee, J. H., Silhavy, J. L., Lee, J. E., Al-Gazali, L., Thomas, S., Davis, E. E., Bielas, S. L., Hill, K. J., Iannicelli, M., Brancati, F., Gabriel, S. B., Russ, C., and 18 others. <strong>Evolutionarily assembled cis-regulatory module at a human ciliopathy locus.</strong> Science 335: 966-969, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22282472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22282472</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22282472[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1213506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22282472">Lee et al. (2012)</a> mapped the mouse Tmem216 gene to a region of chromosome 19 that shares homology of synteny with human chromosome 11q12.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22282472" 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 RNA interference (RNAi) of TMEM216, <a href="#4" class="mim-tip-reference" title="Valente, E. M., Logan, C. V., Mougou-Zerelli, S., Lee, J. H., Silhavy, J. L., Brancati, F., Iannicelli, M., Travaglini, L., Romani, S., Illi, B., Adams, M., Szymanska, K., and 39 others. <strong>Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. (Letter)</strong> Nature Genet. 42: 619-625, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20512146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20512146</a>] [<a href="https://doi.org/10.1038/ng.594" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20512146">Valente et al. (2010)</a> found that knockdown of TMEM216 prevented ciliogenesis in polarized cells and blocked correct docking of centrosomes at the apical cell surface. This was associated with increased RhoA (<a href="/entry/165390">165390</a>) signaling and mislocalization of RhoA. Loss of TMEM216 also caused increased phosphorylation and activation of DVL1 (<a href="/entry/601365">601365</a>). <a href="#4" class="mim-tip-reference" title="Valente, E. M., Logan, C. V., Mougou-Zerelli, S., Lee, J. H., Silhavy, J. L., Brancati, F., Iannicelli, M., Travaglini, L., Romani, S., Illi, B., Adams, M., Szymanska, K., and 39 others. <strong>Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. (Letter)</strong> Nature Genet. 42: 619-625, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20512146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20512146</a>] [<a href="https://doi.org/10.1038/ng.594" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20512146">Valente et al. (2010)</a> presented a working model in which DVL1, RhoA, and TMEM216 serve as part of a complex in the pericentrosomal compartment to mediate cellular polarization and centrosomal apical docking. Hyperactivation of Rho in the absence of TMEM216 might be responsible for the docking defect, as it was rescued by a Rho inhibitor. Finally, immunoprecipitation studies showed the TMEM216 interacted with TMEM67 (<a href="/entry/609884">609884</a>), which is mutant in Meckel syndrome-3 (MKS3; <a href="/entry/607361">607361</a>) and other ciliopathies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20512146" 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="Lee, J. H., Silhavy, J. L., Lee, J. E., Al-Gazali, L., Thomas, S., Davis, E. E., Bielas, S. L., Hill, K. J., Iannicelli, M., Brancati, F., Gabriel, S. B., Russ, C., and 18 others. <strong>Evolutionarily assembled cis-regulatory module at a human ciliopathy locus.</strong> Science 335: 966-969, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22282472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22282472</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22282472[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1213506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22282472">Lee et al. (2012)</a> found that RFX4 mediated coordinated expression of TMEM138 and TMEM216 by binding to a regulatory element within their intergenic region. Knockdown of either Tmem138 or Tmem216 in mouse IMCD3 cells resulted in short cilia and a defect in ciliogenesis. Knockdown of Tmem216 disrupted vesicular trafficking of Tmem138 and Cep290, whereas knockdown of Tmem138 had little effect on vesicular movement of Tmem216. Knockdown of Trappc9 (<a href="/entry/611966">611966</a>), a component of the transport protein particle (TRAPP) II complex, disrupted vesicular tethering of both proteins and reduced ciliogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22282472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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In 13 affected members of 8 Ashkenazi Jewish families with Joubert syndrome-2 (JBTS2; <a href="/entry/608091">608091</a>), <a href="#1" class="mim-tip-reference" title="Edvardson, S., Shaag, A., Zenvirt, S., Erlich, Y., Hannon, G. J., Shanske, A. L., Gomori, J. M., Ekstein, J., Elpeleg, O. <strong>Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation.</strong> Am. J. Hum. Genet. 86: 93-97, 2010. Note: Erratum: 86: 294 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20036350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20036350</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20036350[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.2009.12.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20036350">Edvardson et al. (2010)</a> identified a homozygous mutation in the TMEM216 gene (R73L; <a href="#0001">613277.0001</a>). The carrier rate in this ethnic group was determined to be 1 in 92. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20036350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 14 families with Joubert syndrome-2 and 6 families with Meckel syndrome type 2 (MKS2; <a href="/entry/603194">603194</a>), <a href="#4" class="mim-tip-reference" title="Valente, E. M., Logan, C. V., Mougou-Zerelli, S., Lee, J. H., Silhavy, J. L., Brancati, F., Iannicelli, M., Travaglini, L., Romani, S., Illi, B., Adams, M., Szymanska, K., and 39 others. <strong>Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. (Letter)</strong> Nature Genet. 42: 619-625, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20512146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20512146</a>] [<a href="https://doi.org/10.1038/ng.594" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20512146">Valente et al. (2010)</a> identified 7 different homozygous mutations in the TMEM216 gene (see, e.g., <a href="#0001">613277.0001</a>-<a href="#0004">613277.0004</a>). Ten families with Joubert syndrome were of Ashkenazi Jewish descent and shared the common founder mutation, R73L, previously identified by <a href="#1" class="mim-tip-reference" title="Edvardson, S., Shaag, A., Zenvirt, S., Erlich, Y., Hannon, G. J., Shanske, A. L., Gomori, J. M., Ekstein, J., Elpeleg, O. <strong>Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation.</strong> Am. J. Hum. Genet. 86: 93-97, 2010. Note: Erratum: 86: 294 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20036350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20036350</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20036350[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.2009.12.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20036350">Edvardson et al. (2010)</a>. Two individuals with Joubert syndrome and polydactyly who had the R73L mutation also demonstrated tongue tumors or multiple oral frenula, respectively, reminiscent of orofaciodigital syndrome type VI (OFD6; <a href="/entry/277170">277170</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20512146+20036350" 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>Retinitis Pigmentosa 98</em></strong></p><p>
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In 71 patients from 47 families of African or South Asian ancestry with nonsyndromic retinitis pigmentosa (RP98; <a href="/entry/620996">620996</a>), who were negative for mutation in known retinal dystrophy-associated genes, <a href="#3" class="mim-tip-reference" title="Malka, S., Biswas, P., Berry, A. M., Sangermano, R., Ullah, M., Lin, S., D'Antonio, M., Jestin, A., Jiao, X., Quinodoz, M., Sullivan, L., Gardner, J. C., and 34 others. <strong>Substitution of a single non-coding nucleotide upstream of TMEM216 causes non-syndromic retinitis pigmentosa and is associated with reduced TMEM216 expression.</strong> Am. J. Hum. Genet. 111: 2012-2030, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39191256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39191256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=39191256[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.2024.07.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="39191256">Malka et al. (2024)</a> identified homozygosity for 2 different nucleotide substitutions at the same genomic location, noncoding variants located 69 basepairs upstream of the TMEM216 start codon: in the patients of African ancestry, the mutation was a c.-69G-T transversion (<a href="#0005">613277.0005</a>) and in the patients of South Asian ancestry, the mutation was a c.-69G-A transition (<a href="#0006">613277.0006</a>). In 2 additional families of African ancestry, compound heterozygosity for the c.-69G-T variant and another mutation was present: in 2 affected brothers from Zimbabwe, the second mutation was a large deletion that included exons 1 to 3 of TMEM216, and in a female patient from the Caribbean, the mutation in trans was a splice site variant (<a href="#0007">613277.0007</a>). Both recurrent variants were found in the gnomAD database, with enrichment in the African and South Asian populations, respectively. Haplotype analysis in both cohorts revealed a conserved haplotype that strongly suggested a single founder mutation unique to each group. None of the patients (age range at examination, 5-72 years) exhibited systemic features suggestive of generalized ciliopathy. Functional analysis showed significantly reduced expression with the recurrent variants compared to wildtype TMEM216. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39191256" 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="#2" class="mim-tip-reference" title="Lee, J. H., Silhavy, J. L., Lee, J. E., Al-Gazali, L., Thomas, S., Davis, E. E., Bielas, S. L., Hill, K. J., Iannicelli, M., Brancati, F., Gabriel, S. B., Russ, C., and 18 others. <strong>Evolutionarily assembled cis-regulatory module at a human ciliopathy locus.</strong> Science 335: 966-969, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22282472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22282472</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22282472[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1213506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22282472">Lee et al. (2012)</a> found that the TMEM138 and TMEM216 genes are aligned in a head-to-tail orientation, with a conserved intergenic region, in higher vertebrates only. They determined that the 2 genes came into close association during an ancient chromosomal rearrangement at the amphibian-to-reptile transition about 340 million years ago. Conservation in the intergenic region becomes progressively weaker from human to anolis lizard, and the orthologous genes map to different chromosomes in zebrafish. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22282472" 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="Valente, E. M., Logan, C. V., Mougou-Zerelli, S., Lee, J. H., Silhavy, J. L., Brancati, F., Iannicelli, M., Travaglini, L., Romani, S., Illi, B., Adams, M., Szymanska, K., and 39 others. <strong>Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. (Letter)</strong> Nature Genet. 42: 619-625, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20512146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20512146</a>] [<a href="https://doi.org/10.1038/ng.594" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20512146">Valente et al. (2010)</a> found that knockout of Tmem216 in zebrafish embryos resulted in defects in gastrulation, such as shortened body axis, broad notochords and misshapen somites, similar to defects observed in Tmem67 knockouts. The results indicated an alteration of convergence to the midline and extension along the anteroposterior axis, consistent with a defect in the planar cell polarity pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20512146" 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="Lee, J. H., Silhavy, J. L., Lee, J. E., Al-Gazali, L., Thomas, S., Davis, E. E., Bielas, S. L., Hill, K. J., Iannicelli, M., Brancati, F., Gabriel, S. B., Russ, C., and 18 others. <strong>Evolutionarily assembled cis-regulatory module at a human ciliopathy locus.</strong> Science 335: 966-969, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22282472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22282472</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22282472[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1213506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22282472">Lee et al. (2012)</a> found that knockdown of zebrafish Tmem138 or Tmem216 resulted in similar, but distinct, phenotypes. Knockdown of either gene resulted in pericardial effusion, curved or kinked tail, and gastrulation defects. However, only knockdown of Tmem16 resulted in hydrocephalic brains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22282472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000000220 OR RCV000255378 OR RCV000409114 OR RCV000465185 OR RCV000624413 OR RCV000779066 OR RCV001787358" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000220, RCV000255378, RCV000409114, RCV000465185, RCV000624413, RCV000779066, RCV001787358" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000220...</a>
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<p>In 13 affected members of 8 Ashkenazi Jewish families with Joubert syndrome-2 (JBTS2; <a href="/entry/608091">608091</a>), <a href="#1" class="mim-tip-reference" title="Edvardson, S., Shaag, A., Zenvirt, S., Erlich, Y., Hannon, G. J., Shanske, A. L., Gomori, J. M., Ekstein, J., Elpeleg, O. <strong>Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation.</strong> Am. J. Hum. Genet. 86: 93-97, 2010. Note: Erratum: 86: 294 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20036350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20036350</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20036350[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.2009.12.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20036350">Edvardson et al. (2010)</a> identified a homozygous 218G-T transversion in exon 4 of the TMEM216 gene, resulting in an arg73-to-leu (R73L) substitution in a conserved residue. This mutation was designated ARG12LEU by <a href="#1" class="mim-tip-reference" title="Edvardson, S., Shaag, A., Zenvirt, S., Erlich, Y., Hannon, G. J., Shanske, A. L., Gomori, J. M., Ekstein, J., Elpeleg, O. <strong>Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation.</strong> Am. J. Hum. Genet. 86: 93-97, 2010. Note: Erratum: 86: 294 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20036350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20036350</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20036350[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.2009.12.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20036350">Edvardson et al. (2010)</a>. All of the parents and several unaffected relatives were heterozygous carriers of the mutation, indicating a carrier rate of 1 in 92 in this ethnic group. The phenotype was characterized by neonatal hypotonia, mental retardation, and posterior fossa abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20036350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 12 families with JBTS2, <a href="#4" class="mim-tip-reference" title="Valente, E. M., Logan, C. V., Mougou-Zerelli, S., Lee, J. H., Silhavy, J. L., Brancati, F., Iannicelli, M., Travaglini, L., Romani, S., Illi, B., Adams, M., Szymanska, K., and 39 others. <strong>Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. (Letter)</strong> Nature Genet. 42: 619-625, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20512146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20512146</a>] [<a href="https://doi.org/10.1038/ng.594" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20512146">Valente et al. (2010)</a> identified a homozygous 218G-T transversion in exon 4 of the TMEM216 gene, resulting in an arg73-to-leu (R73L) substitution. Two of the families were from Sicily, and 10 were of Ashkenazi Jewish origin. Haplotype analysis indicated a common founder that dated back at least 20 generations. The carrier frequency in the Ashkenazi Jewish population was determined to be 1 in 100. Two individuals with Joubert syndrome and the R73L mutation who had polydactyly also demonstrated tongue tumors or multiple oral frenula, respectively, reminiscent of orofaciodigital syndrome type VI (OFD6; <a href="/entry/277170">277170</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20512146" 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> rs201108965 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs201108965;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/rs201108965?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=rs201108965" 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=rs201108965" 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 Turkish sibs, 1 with Joubert syndrome-2 (<a href="/entry/608091">608091</a>) and a fetus with Meckel syndrome type 2 (<a href="/entry/603194">603194</a>), <a href="#4" class="mim-tip-reference" title="Valente, E. M., Logan, C. V., Mougou-Zerelli, S., Lee, J. H., Silhavy, J. L., Brancati, F., Iannicelli, M., Travaglini, L., Romani, S., Illi, B., Adams, M., Szymanska, K., and 39 others. <strong>Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. (Letter)</strong> Nature Genet. 42: 619-625, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20512146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20512146</a>] [<a href="https://doi.org/10.1038/ng.594" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20512146">Valente et al. (2010)</a> identified the same homozygous 218G-A transition in exon 4 of the TMEM216 gene, resulting in an arg73-to-his (R73H) substitution. The same codon was affected in other families with Joubert syndrome (R73L; <a href="#0001">613277.0001</a>). The 1-month-old boy with Joubert syndrome had the molar tooth sign, microcornea, cystic kidneys, bile duct proliferation, and polydactyly. The 13-week-old fetus had an encephalocele, polydactyly, and bowing of the long bones. The clinical features clearly overlapped, indicating that the 2 clinical disorders are part of the same spectrum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20512146" 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">rs386833831 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386833831;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=rs386833831" 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=rs386833831" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 fetuses from 2 Tunisian families with Meckel syndrome type 2 (<a href="/entry/603194">603194</a>), <a href="#4" class="mim-tip-reference" title="Valente, E. M., Logan, C. V., Mougou-Zerelli, S., Lee, J. H., Silhavy, J. L., Brancati, F., Iannicelli, M., Travaglini, L., Romani, S., Illi, B., Adams, M., Szymanska, K., and 39 others. <strong>Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. (Letter)</strong> Nature Genet. 42: 619-625, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20512146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20512146</a>] [<a href="https://doi.org/10.1038/ng.594" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20512146">Valente et al. (2010)</a> identified a homozygous 341T-G transversion in exon 5 of the TMEM216 gene, resulting in a leu114-to-arg (L114R) substitution. Common clinical features included cystic kidneys, polydactyly, bile duct proliferation, and bowing of the long bones. Two had meningocele, 1 had anencephaly, and 2 had cleft palate. One of the fetuses also had microphthalmia, intrauterine growth retardation, and hypoplastic external genitalia. Haplotype analysis indicated a common founder for the 2 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20512146" 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">rs386833830 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386833830;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=rs386833830" 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=rs386833830" 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=RCV000000223" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000223" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000223</a>
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<p>In 6 affected fetuses of 3 Palestinian families with Meckel syndrome type 2 (<a href="/entry/603194">603194</a>), <a href="#4" class="mim-tip-reference" title="Valente, E. M., Logan, C. V., Mougou-Zerelli, S., Lee, J. H., Silhavy, J. L., Brancati, F., Iannicelli, M., Travaglini, L., Romani, S., Illi, B., Adams, M., Szymanska, K., and 39 others. <strong>Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. (Letter)</strong> Nature Genet. 42: 619-625, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20512146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20512146</a>] [<a href="https://doi.org/10.1038/ng.594" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20512146">Valente et al. (2010)</a> identified a homozygous 230G-C transversion in the first base of exon 5 of the TMEM216 gene, resulting in a gly77-to-ala (G77A) substitution and leading to the use of an alternative splice site in intron 4, inclusion of an additional 46 bp, and premature termination of the protein. The most common clinical features included encephalocele, cystic kidneys, bile duct proliferation, and polydactyly. Haplotype analysis showed that 2 of the families were related. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20512146" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 42 patients from 38 families of African ancestry with nonsyndromic retinitis pigmentosa (RP98; <a href="/entry/620996">620996</a>), <a href="#3" class="mim-tip-reference" title="Malka, S., Biswas, P., Berry, A. M., Sangermano, R., Ullah, M., Lin, S., D'Antonio, M., Jestin, A., Jiao, X., Quinodoz, M., Sullivan, L., Gardner, J. C., and 34 others. <strong>Substitution of a single non-coding nucleotide upstream of TMEM216 causes non-syndromic retinitis pigmentosa and is associated with reduced TMEM216 expression.</strong> Am. J. Hum. Genet. 111: 2012-2030, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39191256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39191256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=39191256[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.2024.07.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="39191256">Malka et al. (2024)</a> identified homozygosity for a c.-69G-T transversion (c.-69G-T, NM_001173991.3) upstream of the TMEM216 gene. In 3 patients from 2 additional families with RP, affected individuals were compound heterozygotes: in the female proband from a Caribbean family (M1), the second mutation was a splice site variant (c.35-2A-G; <a href="#0007">613277.0007</a>), and in 2 affected brothers from a Zimbabwean family (M2), the second mutation was a large deletion that included exons 1 to 3 of TMEM216 and the upstream region. The recurrent c.-69G-T variant was found in the gnomAD database, with enrichment in the African population (minor allele frequency, 0.005); haplotype analysis in affected individuals revealed a conserved haplotype that strongly suggested a single founder mutation unique to the population. Dual luciferase reporter assay showed significant downregulation with the c.-69G-T variant compared to wildtype control, and RT-qPCR in 2 patients confirmed a significant reduction (51%) in TMEM216 expression compared to wildtype individuals. Read depth analysis of a cDNA sample from a heterozygous parent suggested reduced but not abrogated expression with the c.-69G-T variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39191256" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002577274 OR RCV004776308" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002577274, RCV004776308" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002577274...</a>
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<p>In 29 patients from 9 families of South Asian origin (8 Pakistani and 1 Bangladeshi) with nonsyndromic retinitis pigmentosa (RP98; <a href="/entry/620996">620996</a>), <a href="#3" class="mim-tip-reference" title="Malka, S., Biswas, P., Berry, A. M., Sangermano, R., Ullah, M., Lin, S., D'Antonio, M., Jestin, A., Jiao, X., Quinodoz, M., Sullivan, L., Gardner, J. C., and 34 others. <strong>Substitution of a single non-coding nucleotide upstream of TMEM216 causes non-syndromic retinitis pigmentosa and is associated with reduced TMEM216 expression.</strong> Am. J. Hum. Genet. 111: 2012-2030, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39191256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39191256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=39191256[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.2024.07.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="39191256">Malka et al. (2024)</a> identified homozygosity for a c.-69G-A transition (c.69G-A, NM_001173991.3) upstream of the TMEM216 gene. Dual luciferase reporter assay showed significant downregulation with the c.-69G-A variant compared to wildtype control. The recurrent c.-69G-A variant was found in the gnomAD database, with enrichment in the South Asian population (minor allele frequency, 0.00095); haplotype analysis in affected individuals revealed a conserved haplotype that strongly suggested a single founder mutation unique to the population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39191256" 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>.0007 RETINITIS PIGMENTOSA 98</strong>
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TMEM216, c.35-2A-G
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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> rs1057517528 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057517528;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/rs1057517528?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=rs1057517528" 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=rs1057517528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000409368 OR RCV000410496 OR RCV002524628 OR RCV004776284 OR RCV005049540" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000409368, RCV000410496, RCV002524628, RCV004776284, RCV005049540" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000409368...</a>
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<p>For discussion of the c.35-2A-G transition (c.35-2A-G, NM_001173991.3) in the TMEM216 gene that was found in compound heterozygous state in the female proband from a family of Caribbean ancestry (M1) with nonsyndromic retinitis pigmentosa (RP98; <a href="/entry/620996">620996</a>) by <a href="#3" class="mim-tip-reference" title="Malka, S., Biswas, P., Berry, A. M., Sangermano, R., Ullah, M., Lin, S., D'Antonio, M., Jestin, A., Jiao, X., Quinodoz, M., Sullivan, L., Gardner, J. C., and 34 others. <strong>Substitution of a single non-coding nucleotide upstream of TMEM216 causes non-syndromic retinitis pigmentosa and is associated with reduced TMEM216 expression.</strong> Am. J. Hum. Genet. 111: 2012-2030, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39191256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39191256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=39191256[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.2024.07.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="39191256">Malka et al. (2024)</a>, see <a href="#0005">613277.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39191256" 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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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Edvardson2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Edvardson, S., Shaag, A., Zenvirt, S., Erlich, Y., Hannon, G. J., Shanske, A. L., Gomori, J. M., Ekstein, J., Elpeleg, O.
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<strong>Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation.</strong>
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Am. J. Hum. Genet. 86: 93-97, 2010. Note: Erratum: 86: 294 only, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20036350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20036350</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20036350[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=20036350" 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.2009.12.007" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
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<a id="Lee2012" class="mim-anchor"></a>
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Lee, J. H., Silhavy, J. L., Lee, J. E., Al-Gazali, L., Thomas, S., Davis, E. E., Bielas, S. L., Hill, K. J., Iannicelli, M., Brancati, F., Gabriel, S. B., Russ, C., and 18 others.
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<strong>Evolutionarily assembled cis-regulatory module at a human ciliopathy locus.</strong>
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Science 335: 966-969, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22282472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22282472</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22282472[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=22282472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1213506" target="_blank">Full Text</a>]
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<a id="Malka2024" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Malka, S., Biswas, P., Berry, A. M., Sangermano, R., Ullah, M., Lin, S., D'Antonio, M., Jestin, A., Jiao, X., Quinodoz, M., Sullivan, L., Gardner, J. C., and 34 others.
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|
<strong>Substitution of a single non-coding nucleotide upstream of TMEM216 causes non-syndromic retinitis pigmentosa and is associated with reduced TMEM216 expression.</strong>
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Am. J. Hum. Genet. 111: 2012-2030, 2024.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39191256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39191256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=39191256[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=39191256" 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.2024.07.020" target="_blank">Full Text</a>]
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<a id="Valente2010" class="mim-anchor"></a>
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Valente, E. M., Logan, C. V., Mougou-Zerelli, S., Lee, J. H., Silhavy, J. L., Brancati, F., Iannicelli, M., Travaglini, L., Romani, S., Illi, B., Adams, M., Szymanska, K., and 39 others.
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<strong>Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. (Letter)</strong>
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Nature Genet. 42: 619-625, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20512146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20512146</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20512146" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.594" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 10/29/2024
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Patricia A. Hartz - updated : 1/30/2012<br>Cassandra L. Kniffin - updated : 9/7/2010<br>Cassandra L. Kniffin - updated : 3/1/2010
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Creation Date:
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Patricia A. Hartz : 2/23/2010
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carol : 10/29/2024
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carol : 09/12/2013<br>carol : 3/9/2012<br>mgross : 1/30/2012<br>terry : 1/30/2012<br>carol : 11/22/2011<br>terry : 11/18/2010<br>wwang : 9/14/2010<br>wwang : 9/14/2010<br>ckniffin : 9/7/2010<br>carol : 3/19/2010<br>wwang : 3/2/2010<br>ckniffin : 3/1/2010<br>mgross : 2/23/2010
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<strong>*</strong> 613277
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TRANSMEMBRANE PROTEIN 216; TMEM216
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<strong><em>HGNC Approved Gene Symbol: TMEM216</em></strong>
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Cytogenetic location: 11q12.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:61,392,587-61,398,846 </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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Location
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Phenotype
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Inheritance
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11q12.2
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<td>
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<span class="mim-font">
|
|
Joubert syndrome 2
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|
</span>
|
|
</td>
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<td>
|
|
<span class="mim-font">
|
|
608091
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
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|
|
|
|
|
|
|
</tr>
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|
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|
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|
|
|
|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Meckel syndrome 2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
603194
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Retinitis pigmentosa 98
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
620996
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
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|
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|
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|
</tbody>
|
|
</table>
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</div>
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</div>
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<div>
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<br />
|
|
</div>
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<div>
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|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
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</div>
|
|
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<span class="mim-text-font">
|
|
<p>TMEM216 is required for the assembly and function of cilia (Lee et al., 2012). </p>
|
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</span>
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<div>
|
|
<br />
|
|
</div>
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|
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<span class="mim-text-font">
|
|
<p>By searching for genes in a region of chromosome 11 linked to Joubert syndrome-2 (JBTS2; 608091), Edvardson et al. (2010) identified TMEM216. The deduced 87-amino acid protein has 2 transmembrane domains. </p><p>Valente et al. (2010) identified a 1.4-kb TMEM216 mRNA in fetal tissue. Screening of a human fetal brain cDNA library identified 4 major splice isoforms, the longest and most prevalent predicting a 148-amino acid full-length protein with 4 transmembrane domains. There was also extensive alternative splicing, resulting in transcripts encoding 3 very short proteins of 25, 30, 34 amino acids, respectively. In situ hybridization of human embryonic tissues showed TMEM216 expression in the central nervous system, limb bud, kidney, and cartilage. Specific localization was also found in mouse inner medullary collecting duct cells, human retinal pigment epithelium, and proximal renal tubule, and TMEM216 localized to the base of the primary cilium or adjacent basal body. </p><p>Using expression profiling, Lee et al. (2012) showed that TMEM216 was expressed in all tissues examined. In situ hybridization of human embryos at 4 to 8 weeks' gestation revealed ubiquitous TMEM216 expression that increased with time. TMEM216 expression appeared to parallel that of TMEM138, which is closely linked to TMEM216, in all tissues examined. Immunohistochemical analysis of mouse IMCD3 cells and transfected COS-7 cells revealed that Tmem216 localized to basal body and to the Golgi apparatus surrounding the base of cilium and that Tmem138 localized to ciliary axoneme/basal body. The 2 proteins also appeared to localize to different vesicle pools that moved toward the primary cilia over time. Tmem138 vesicles, but not Tmem216 vesicles, colocalized with endogenous Cep290 (610142) in IMCD3 cells. </p><p>Malka et al. (2024) analyzed expression of TMEM216 in human tissues in the GTEx database and observed significantly higher levels of TMEM216 transcript in the peripheral retina compared to levels recorded from other tissues in the GTEx database. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Edvardson et al. (2010) determined that the TMEM216 gene contains 3 coding exons. Valente et al. (2010) determined that the TMEM216 gene contains 6 exons with alternative splicing of exon 2. </p><p>Lee et al. (2012) determined that the TMEM216 gene contains 5 exons. The 23-kb intergenic region between TMEM138 and TMEM216 contains a functional conserved RFX4 (603958)-binding site. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>By genomic sequence analysis, Edvardson et al. (2010) mapped the TMEM216 gene to chromosome 11q13. </p><p>By genomic sequence analysis, Lee et al. (2012) mapped the TMEM216 gene to chromosome 11q12.2, 23 kb from the TMEM138 gene. TMEM216 and TMEM138 are in a head-to-tail orientation. </p><p>Lee et al. (2012) mapped the mouse Tmem216 gene to a region of chromosome 19 that shares homology of synteny with human chromosome 11q12.2. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>By RNA interference (RNAi) of TMEM216, Valente et al. (2010) found that knockdown of TMEM216 prevented ciliogenesis in polarized cells and blocked correct docking of centrosomes at the apical cell surface. This was associated with increased RhoA (165390) signaling and mislocalization of RhoA. Loss of TMEM216 also caused increased phosphorylation and activation of DVL1 (601365). Valente et al. (2010) presented a working model in which DVL1, RhoA, and TMEM216 serve as part of a complex in the pericentrosomal compartment to mediate cellular polarization and centrosomal apical docking. Hyperactivation of Rho in the absence of TMEM216 might be responsible for the docking defect, as it was rescued by a Rho inhibitor. Finally, immunoprecipitation studies showed the TMEM216 interacted with TMEM67 (609884), which is mutant in Meckel syndrome-3 (MKS3; 607361) and other ciliopathies. </p><p>Lee et al. (2012) found that RFX4 mediated coordinated expression of TMEM138 and TMEM216 by binding to a regulatory element within their intergenic region. Knockdown of either Tmem138 or Tmem216 in mouse IMCD3 cells resulted in short cilia and a defect in ciliogenesis. Knockdown of Tmem216 disrupted vesicular trafficking of Tmem138 and Cep290, whereas knockdown of Tmem138 had little effect on vesicular movement of Tmem216. Knockdown of Trappc9 (611966), a component of the transport protein particle (TRAPP) II complex, disrupted vesicular tethering of both proteins and reduced ciliogenesis. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Joubert Syndrome 2 and Meckel Syndrome 2</em></strong></p><p>
|
|
In 13 affected members of 8 Ashkenazi Jewish families with Joubert syndrome-2 (JBTS2; 608091), Edvardson et al. (2010) identified a homozygous mutation in the TMEM216 gene (R73L; 613277.0001). The carrier rate in this ethnic group was determined to be 1 in 92. </p><p>In affected members of 14 families with Joubert syndrome-2 and 6 families with Meckel syndrome type 2 (MKS2; 603194), Valente et al. (2010) identified 7 different homozygous mutations in the TMEM216 gene (see, e.g., 613277.0001-613277.0004). Ten families with Joubert syndrome were of Ashkenazi Jewish descent and shared the common founder mutation, R73L, previously identified by Edvardson et al. (2010). Two individuals with Joubert syndrome and polydactyly who had the R73L mutation also demonstrated tongue tumors or multiple oral frenula, respectively, reminiscent of orofaciodigital syndrome type VI (OFD6; 277170). </p><p><strong><em>Retinitis Pigmentosa 98</em></strong></p><p>
|
|
In 71 patients from 47 families of African or South Asian ancestry with nonsyndromic retinitis pigmentosa (RP98; 620996), who were negative for mutation in known retinal dystrophy-associated genes, Malka et al. (2024) identified homozygosity for 2 different nucleotide substitutions at the same genomic location, noncoding variants located 69 basepairs upstream of the TMEM216 start codon: in the patients of African ancestry, the mutation was a c.-69G-T transversion (613277.0005) and in the patients of South Asian ancestry, the mutation was a c.-69G-A transition (613277.0006). In 2 additional families of African ancestry, compound heterozygosity for the c.-69G-T variant and another mutation was present: in 2 affected brothers from Zimbabwe, the second mutation was a large deletion that included exons 1 to 3 of TMEM216, and in a female patient from the Caribbean, the mutation in trans was a splice site variant (613277.0007). Both recurrent variants were found in the gnomAD database, with enrichment in the African and South Asian populations, respectively. Haplotype analysis in both cohorts revealed a conserved haplotype that strongly suggested a single founder mutation unique to each group. None of the patients (age range at examination, 5-72 years) exhibited systemic features suggestive of generalized ciliopathy. Functional analysis showed significantly reduced expression with the recurrent variants compared to wildtype TMEM216. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Evolution</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Lee et al. (2012) found that the TMEM138 and TMEM216 genes are aligned in a head-to-tail orientation, with a conserved intergenic region, in higher vertebrates only. They determined that the 2 genes came into close association during an ancient chromosomal rearrangement at the amphibian-to-reptile transition about 340 million years ago. Conservation in the intergenic region becomes progressively weaker from human to anolis lizard, and the orthologous genes map to different chromosomes in zebrafish. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Valente et al. (2010) found that knockout of Tmem216 in zebrafish embryos resulted in defects in gastrulation, such as shortened body axis, broad notochords and misshapen somites, similar to defects observed in Tmem67 knockouts. The results indicated an alteration of convergence to the midline and extension along the anteroposterior axis, consistent with a defect in the planar cell polarity pathway. </p><p>Lee et al. (2012) found that knockdown of zebrafish Tmem138 or Tmem216 resulted in similar, but distinct, phenotypes. Knockdown of either gene resulted in pericardial effusion, curved or kinked tail, and gastrulation defects. However, only knockdown of Tmem16 resulted in hydrocephalic brains. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>7 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 JOUBERT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM216, ARG73LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs201108965,
|
|
|
|
|
|
gnomAD: rs201108965,
|
|
|
|
|
|
ClinVar: RCV000000220, RCV000255378, RCV000409114, RCV000465185, RCV000624413, RCV000779066, RCV001787358
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 13 affected members of 8 Ashkenazi Jewish families with Joubert syndrome-2 (JBTS2; 608091), Edvardson et al. (2010) identified a homozygous 218G-T transversion in exon 4 of the TMEM216 gene, resulting in an arg73-to-leu (R73L) substitution in a conserved residue. This mutation was designated ARG12LEU by Edvardson et al. (2010). All of the parents and several unaffected relatives were heterozygous carriers of the mutation, indicating a carrier rate of 1 in 92 in this ethnic group. The phenotype was characterized by neonatal hypotonia, mental retardation, and posterior fossa abnormalities. </p><p>In affected members of 12 families with JBTS2, Valente et al. (2010) identified a homozygous 218G-T transversion in exon 4 of the TMEM216 gene, resulting in an arg73-to-leu (R73L) substitution. Two of the families were from Sicily, and 10 were of Ashkenazi Jewish origin. Haplotype analysis indicated a common founder that dated back at least 20 generations. The carrier frequency in the Ashkenazi Jewish population was determined to be 1 in 100. Two individuals with Joubert syndrome and the R73L mutation who had polydactyly also demonstrated tongue tumors or multiple oral frenula, respectively, reminiscent of orofaciodigital syndrome type VI (OFD6; 277170). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 JOUBERT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
MECKEL SYNDROME, TYPE 2, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM216, ARG73HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs201108965,
|
|
|
|
|
|
gnomAD: rs201108965,
|
|
|
|
|
|
ClinVar: RCV000000221, RCV000024013, RCV001038780, RCV005049302
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Turkish sibs, 1 with Joubert syndrome-2 (608091) and a fetus with Meckel syndrome type 2 (603194), Valente et al. (2010) identified the same homozygous 218G-A transition in exon 4 of the TMEM216 gene, resulting in an arg73-to-his (R73H) substitution. The same codon was affected in other families with Joubert syndrome (R73L; 613277.0001). The 1-month-old boy with Joubert syndrome had the molar tooth sign, microcornea, cystic kidneys, bile duct proliferation, and polydactyly. The 13-week-old fetus had an encephalocele, polydactyly, and bowing of the long bones. The clinical features clearly overlapped, indicating that the 2 clinical disorders are part of the same spectrum. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 MECKEL SYNDROME, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM216, LEU114ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs386833831,
|
|
|
|
|
|
|
|
ClinVar: RCV000000222
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 fetuses from 2 Tunisian families with Meckel syndrome type 2 (603194), Valente et al. (2010) identified a homozygous 341T-G transversion in exon 5 of the TMEM216 gene, resulting in a leu114-to-arg (L114R) substitution. Common clinical features included cystic kidneys, polydactyly, bile duct proliferation, and bowing of the long bones. Two had meningocele, 1 had anencephaly, and 2 had cleft palate. One of the fetuses also had microphthalmia, intrauterine growth retardation, and hypoplastic external genitalia. Haplotype analysis indicated a common founder for the 2 families. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 MECKEL SYNDROME, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM216, GLY77ALA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs386833830,
|
|
|
|
|
|
|
|
ClinVar: RCV000000223
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 6 affected fetuses of 3 Palestinian families with Meckel syndrome type 2 (603194), Valente et al. (2010) identified a homozygous 230G-C transversion in the first base of exon 5 of the TMEM216 gene, resulting in a gly77-to-ala (G77A) substitution and leading to the use of an alternative splice site in intron 4, inclusion of an additional 46 bp, and premature termination of the protein. The most common clinical features included encephalocele, cystic kidneys, bile duct proliferation, and polydactyly. Haplotype analysis showed that 2 of the families were related. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 RETINITIS PIGMENTOSA 98</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM216, c.-69G-T
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
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<p>In 42 patients from 38 families of African ancestry with nonsyndromic retinitis pigmentosa (RP98; 620996), Malka et al. (2024) identified homozygosity for a c.-69G-T transversion (c.-69G-T, NM_001173991.3) upstream of the TMEM216 gene. In 3 patients from 2 additional families with RP, affected individuals were compound heterozygotes: in the female proband from a Caribbean family (M1), the second mutation was a splice site variant (c.35-2A-G; 613277.0007), and in 2 affected brothers from a Zimbabwean family (M2), the second mutation was a large deletion that included exons 1 to 3 of TMEM216 and the upstream region. The recurrent c.-69G-T variant was found in the gnomAD database, with enrichment in the African population (minor allele frequency, 0.005); haplotype analysis in affected individuals revealed a conserved haplotype that strongly suggested a single founder mutation unique to the population. Dual luciferase reporter assay showed significant downregulation with the c.-69G-T variant compared to wildtype control, and RT-qPCR in 2 patients confirmed a significant reduction (51%) in TMEM216 expression compared to wildtype individuals. Read depth analysis of a cDNA sample from a heterozygous parent suggested reduced but not abrogated expression with the c.-69G-T variant. </p>
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<span class="mim-font">
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<strong>.0006 RETINITIS PIGMENTOSA 98</strong>
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<span class="mim-text-font">
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TMEM216, c.-69G-A
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<br />
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ClinVar: RCV002577274, RCV004776308
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<p>In 29 patients from 9 families of South Asian origin (8 Pakistani and 1 Bangladeshi) with nonsyndromic retinitis pigmentosa (RP98; 620996), Malka et al. (2024) identified homozygosity for a c.-69G-A transition (c.69G-A, NM_001173991.3) upstream of the TMEM216 gene. Dual luciferase reporter assay showed significant downregulation with the c.-69G-A variant compared to wildtype control. The recurrent c.-69G-A variant was found in the gnomAD database, with enrichment in the South Asian population (minor allele frequency, 0.00095); haplotype analysis in affected individuals revealed a conserved haplotype that strongly suggested a single founder mutation unique to the population. </p>
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<h4>
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<span class="mim-font">
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<strong>.0007 RETINITIS PIGMENTOSA 98</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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TMEM216, c.35-2A-G
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<br />
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SNP: rs1057517528,
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gnomAD: rs1057517528,
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ClinVar: RCV000409368, RCV000410496, RCV002524628, RCV004776284, RCV005049540
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<span class="mim-text-font">
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<p>For discussion of the c.35-2A-G transition (c.35-2A-G, NM_001173991.3) in the TMEM216 gene that was found in compound heterozygous state in the female proband from a family of Caribbean ancestry (M1) with nonsyndromic retinitis pigmentosa (RP98; 620996) by Malka et al. (2024), see 613277.0005. </p>
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<h4>
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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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<p />
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</div>
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Edvardson, S., Shaag, A., Zenvirt, S., Erlich, Y., Hannon, G. J., Shanske, A. L., Gomori, J. M., Ekstein, J., Elpeleg, O.
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<strong>Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation.</strong>
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Am. J. Hum. Genet. 86: 93-97, 2010. Note: Erratum: 86: 294 only, 2010.
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[PubMed: 20036350]
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[Full Text: https://doi.org/10.1016/j.ajhg.2009.12.007]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Lee, J. H., Silhavy, J. L., Lee, J. E., Al-Gazali, L., Thomas, S., Davis, E. E., Bielas, S. L., Hill, K. J., Iannicelli, M., Brancati, F., Gabriel, S. B., Russ, C., and 18 others.
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<strong>Evolutionarily assembled cis-regulatory module at a human ciliopathy locus.</strong>
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Science 335: 966-969, 2012.
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[PubMed: 22282472]
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[Full Text: https://doi.org/10.1126/science.1213506]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Malka, S., Biswas, P., Berry, A. M., Sangermano, R., Ullah, M., Lin, S., D'Antonio, M., Jestin, A., Jiao, X., Quinodoz, M., Sullivan, L., Gardner, J. C., and 34 others.
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<strong>Substitution of a single non-coding nucleotide upstream of TMEM216 causes non-syndromic retinitis pigmentosa and is associated with reduced TMEM216 expression.</strong>
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Am. J. Hum. Genet. 111: 2012-2030, 2024.
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[PubMed: 39191256]
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[Full Text: https://doi.org/10.1016/j.ajhg.2024.07.020]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Valente, E. M., Logan, C. V., Mougou-Zerelli, S., Lee, J. H., Silhavy, J. L., Brancati, F., Iannicelli, M., Travaglini, L., Romani, S., Illi, B., Adams, M., Szymanska, K., and 39 others.
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<strong>Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. (Letter)</strong>
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Nature Genet. 42: 619-625, 2010.
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[PubMed: 20512146]
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[Full Text: https://doi.org/10.1038/ng.594]
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Marla J. F. O'Neill - updated : 10/29/2024<br>Patricia A. Hartz - updated : 1/30/2012<br>Cassandra L. Kniffin - updated : 9/7/2010<br>Cassandra L. Kniffin - updated : 3/1/2010
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Patricia A. Hartz : 2/23/2010
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