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Entry
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- *609884 - TRANSMEMBRANE PROTEIN 67; TMEM67
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- OMIM
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<p>
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<span class="h4">*609884</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</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/609884">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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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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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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<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=ENSG00000164953;t=ENST00000453321" 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=91147" 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=609884" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</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=ENSG00000164953;t=ENST00000453321" 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_001142301,NM_153704,NR_024522,XM_006716686,XM_011517363,XM_047422409,XM_047422410,XR_001745619,XR_007060760,XR_007060761,XR_007060762,XR_007060763,XR_428387,XR_928360" 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_153704" 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=609884" 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=11324&isoform_id=11324_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/TMEM67" 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/23271019,57997579,119612107,119612108,119612109,187281580,193787301,193787756,194387346,214830753,317373389,578816249,767953785,957951705,957951707,957951710,2217373723,2217373726,2462621587,2462621589,2462621591,2462621593" 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/Q5HYA8" 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=91147" 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=ENSG00000164953;t=ENST00000453321" 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=TMEM67" 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=TMEM67" 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+91147" 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/TMEM67" 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:91147" 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/91147" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr8&hgg_gene=ENST00000453321.8&hgg_start=93754844&hgg_end=93832653&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:28396" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:28396" 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=609884[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=609884[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/TMEM67/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/ENSG00000164953" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=TMEM67" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=TMEM67" 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=TMEM67" 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=TMEM67&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/PA142670780" 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:28396" 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/FBgn0038814.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:1923928" 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/TMEM67#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:1923928" 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/91147/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002176/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=91147" 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=WBGene00018042;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-080716-1" 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=TMEM67&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 723999009<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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609884
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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 67; TMEM67
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</span>
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</h3>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
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MKS3 GENE<br />
|
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MECKELIN
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TMEM67" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TMEM67</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">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/8/405?start=-3&limit=10&highlight=405">8q22.1</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr8:93754844-93832653&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">8:93,754,844-93,832,653</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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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">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=602152,615991,216360,610688,607361,613550" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="6">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/8/405?start=-3&limit=10&highlight=405">
|
|
8q22.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
?RHYNS syndrome
|
|
|
|
<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
|
</span>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/602152"> 602152 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
{Bardet-Biedl syndrome 14, modifier of}
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/615991"> 615991 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
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<p><a href="#17" class="mim-tip-reference" title="Smith, U. R., Consugar, M., Tee, L. J., McKee, B. M., Maina, E. N., Whelan, S., Morgan, N. V., Goranson, E., Gissen, P., Lilliquist, S., Aligianis, I. A., Ward, C. J., and 19 others. <strong>The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and wpk rat.</strong> Nature Genet. 38: 191-196, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16415887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16415887</a>] [<a href="https://doi.org/10.1038/ng1713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16415887">Smith et al. (2006)</a> refined mapping of a Meckel syndrome locus (MKS3; <a href="/entry/607361">607361</a>) to a 12.67-Mb interval on chromosome 8q21.13-q22.1, which is syntenic to the Wpk locus in rat. Positional cloning of the Wpk gene suggested an MKS3 candidate gene, TMEM67 (transmembrane protein-67). The human TMEM67 gene encodes a deduced 995-amino acid protein, which the authors called meckelin, with a calculated unglycosylated mass of 108 kD. Human and rat meckelin share 84% identity. Meckelin was predicted to contain a signal peptide, at least 2 cysteine-rich repeats, and a 490-residue extracellular region with 4 N-linked glycosylated sites, followed by 7 transmembrane domains and a 30-residue cytoplasmic tail. RNA blotting identified a primary transcript of 4.0 kb and a weaker product of 4.5 kb expressed in all adult and fetal human tissues tested. Real-time quantitative PCR analysis of human embryonic tissues detected highest expression in spinal cord and moderate levels in adrenal tissue, brain, and kidney. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16415887" 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 in situ hybridization with human embryos, <a href="#8" class="mim-tip-reference" title="Dawe, H. R., Smith, U. M., Cullinane, A. R., Gerrelli, D., Cox, P., Badano, J. L., Blair-Reid, S., Sriram, N., Katsanis, N., Attie-Bitach, T., Afford, S. C., Copp, A. J., Kelly, D. A., Gull, K., Johnson, C. A. <strong>The Meckel-Gruber syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation.</strong> Hum. Molec. Genet. 16: 173-186, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17185389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17185389</a>] [<a href="https://doi.org/10.1093/hmg/ddl459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17185389">Dawe et al. (2007)</a> found that meckelin was expressed in kidney, liver, retina, hindbrain, developing sphenoid bone, and the brain midline. Intense expression was also detected in cartilage of developing limbs, particularly in the digits. Immunohistochemical analysis of 18- to 20-week-old human fetal kidneys detected moderate to high expression of meckelin and MKS1 (<a href="/entry/609883">609883</a>) at the proximal renal tubule epithelia, but not at glomeruli. In liver, these proteins were also expressed at the biliary epithelium of larger bile ducts, but not in hepatocytes. In HEK293 cells, meckelin was expressed at the cell border and colocalized with alpha-tubulin (see <a href="/entry/602529">602529</a>) at primary cilia. Western blot analysis detected meckelin at an apparent molecular mass of 120 kD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17185389" 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 sequence analysis, <a href="#17" class="mim-tip-reference" title="Smith, U. R., Consugar, M., Tee, L. J., McKee, B. M., Maina, E. N., Whelan, S., Morgan, N. V., Goranson, E., Gissen, P., Lilliquist, S., Aligianis, I. A., Ward, C. J., and 19 others. <strong>The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and wpk rat.</strong> Nature Genet. 38: 191-196, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16415887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16415887</a>] [<a href="https://doi.org/10.1038/ng1713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16415887">Smith et al. (2006)</a> mapped the TMEM67 gene to chromosome 8q21.13-q22.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16415887" 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>Using RNA interference, <a href="#8" class="mim-tip-reference" title="Dawe, H. R., Smith, U. M., Cullinane, A. R., Gerrelli, D., Cox, P., Badano, J. L., Blair-Reid, S., Sriram, N., Katsanis, N., Attie-Bitach, T., Afford, S. C., Copp, A. J., Kelly, D. A., Gull, K., Johnson, C. A. <strong>The Meckel-Gruber syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation.</strong> Hum. Molec. Genet. 16: 173-186, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17185389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17185389</a>] [<a href="https://doi.org/10.1093/hmg/ddl459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17185389">Dawe et al. (2007)</a> found that knockdown of either Mks1 or Mks3 in mouse inner medullary IMCD-3 cells blocked centriole migration to the apical membrane and formation of the primary cilium. Coimmunoprecipitation experiments showed that wildtype Mks1 and Mks3 interacted, and knockdown of either Mks1 or Mks3 in IMCD-3 cells decreased the formation of highly branched structures and tubules in 3-dimensional cultures. <a href="#8" class="mim-tip-reference" title="Dawe, H. R., Smith, U. M., Cullinane, A. R., Gerrelli, D., Cox, P., Badano, J. L., Blair-Reid, S., Sriram, N., Katsanis, N., Attie-Bitach, T., Afford, S. C., Copp, A. J., Kelly, D. A., Gull, K., Johnson, C. A. <strong>The Meckel-Gruber syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation.</strong> Hum. Molec. Genet. 16: 173-186, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17185389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17185389</a>] [<a href="https://doi.org/10.1093/hmg/ddl459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17185389">Dawe et al. (2007)</a> concluded that MKS1 and MKS3 have roles in ciliogenesis and renal tubulogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17185389" 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="#18" class="mim-tip-reference" title="Tammachote, R., Hommerding, C. J., Sinders, R. M., Miller, C. A., Czarnecki, P. G., Leightner, A. C., Salisbury, J. L., Ward, C. J., Torres, V. E., Gattone, V. H., II, Harris, P. C. <strong>Ciliary and centrosomal defects associated with mutation and depletion of the Meckel syndrome genes MKS1 and MKS3.</strong> Hum. Molec. Genet. 18: 3311-3323, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19515853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19515853</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19515853[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19515853">Tammachote et al. (2009)</a> showed that kidney tissue and cells from MKS1 (<a href="/entry/249000">249000</a>) and MKS3 patients showed defects in centrosome and cilia number, including multiciliated respiratory-like epithelia, and longer cilia. Stable shRNA knockdown of Mks1 and Mks3 in IMCD-3 cells induced multiciliated and multicentrosomal phenotypes. MKS1 and MKS3 functions are required for ciliary structure and function, including a role in regulating length and appropriate number through modulating centrosome duplication. <a href="#18" class="mim-tip-reference" title="Tammachote, R., Hommerding, C. J., Sinders, R. M., Miller, C. A., Czarnecki, P. G., Leightner, A. C., Salisbury, J. L., Ward, C. J., Torres, V. E., Gattone, V. H., II, Harris, P. C. <strong>Ciliary and centrosomal defects associated with mutation and depletion of the Meckel syndrome genes MKS1 and MKS3.</strong> Hum. Molec. Genet. 18: 3311-3323, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19515853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19515853</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19515853[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19515853">Tammachote et al. (2009)</a> concluded that MKS1 and MKS3 are ciliopathies, with new cilia-related eye and sperm phenotypes defined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19515853" 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="#20" class="mim-tip-reference" title="Williams, C. L., Li, C., Kida, K., Inglis, P. N., Mohan, S., Semenec, L., Bialas, N. J., Stupay, R. M., Chen, N., Blacque, O. E., Yoder, B. K., Leroux, M. R. <strong>MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis.</strong> J. Cell. Biol. 192: 1023-1041, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21422230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21422230</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21422230[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1083/jcb.201012116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21422230">Williams et al. (2011)</a> showed that the conserved proteins Mks1, Mksr1 (B9D1; <a href="/entry/614144">614144</a>), Mksr2 (B9D2; <a href="/entry/611951">611951</a>), Tmem67, Rpgrip1l (<a href="/entry/610937">610937</a>), Cc2d2a (<a href="/entry/612013">612013</a>), Nphp1 (<a href="/entry/607100">607100</a>), and Nphp4 (<a href="/entry/607215">607215</a>) functioned at an early stage of ciliogenesis in C. elegans. These 8 proteins localized to the ciliary transition zone and established attachments between the basal body and transition zone membrane. They also provided a docking site that restricted vesicle fusion to vesicles containing ciliary proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21422230" 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 yeast 2-hybrid and immunoprecipitation analyses, <a href="#2" class="mim-tip-reference" title="Adams, M., Simms, R. J., Abdelhamed, Z., Dawe, H. R., Szymanska, K., Logan, C. V., Wheway, G., Pitt, E., Gull, K., Knowles, M. A., Blair, E., Cross, S. H., Sayer, J. A., Johnson, C. A. <strong>A meckelin-filamin A interaction mediates ciliogenesis.</strong> Hum. Molec. Genet. 21: 1272-1286, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22121117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22121117</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22121117[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddr557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22121117">Adams et al. (2012)</a> found that the C-terminal cytoplasmic tail of meckelin interacted with filamin A (FLNA; <a href="/entry/300017">300017</a>). Loss of filamin A or meckelin in immortalized fibroblasts from patients with null mutations in the genes or by small interfering RNA in mouse IMCD3 cells resulted in similar cellular phenotypes, including abnormal basal body positioning and ciliogenesis, aberrant remodeling of the actin cytoskeleton, deregulation of RHOA (<a href="/entry/165390">165390</a>) activity, and hyperactivation of canonical Wnt (see <a href="/entry/606359">606359</a>) signaling. <a href="#2" class="mim-tip-reference" title="Adams, M., Simms, R. J., Abdelhamed, Z., Dawe, H. R., Szymanska, K., Logan, C. V., Wheway, G., Pitt, E., Gull, K., Knowles, M. A., Blair, E., Cross, S. H., Sayer, J. A., Johnson, C. A. <strong>A meckelin-filamin A interaction mediates ciliogenesis.</strong> Hum. Molec. Genet. 21: 1272-1286, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22121117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22121117</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22121117[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddr557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22121117">Adams et al. (2012)</a> concluded that the meckelin-filamin A signaling axis is a key regulator of ciliogenesis and normal Wnt signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22121117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Meckel Syndrome 3</em></strong></p><p>
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In 5 consanguineous families with Meckel syndrome linked to chromosome 8q21.13-q22.1 (MKS3; <a href="/entry/607361">607361</a>), <a href="#17" class="mim-tip-reference" title="Smith, U. R., Consugar, M., Tee, L. J., McKee, B. M., Maina, E. N., Whelan, S., Morgan, N. V., Goranson, E., Gissen, P., Lilliquist, S., Aligianis, I. A., Ward, C. J., and 19 others. <strong>The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and wpk rat.</strong> Nature Genet. 38: 191-196, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16415887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16415887</a>] [<a href="https://doi.org/10.1038/ng1713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16415887">Smith et al. (2006)</a> detected 5 different homozygous mutations in the TMEM67 gene (<a href="#0001">609884.0001</a>-<a href="#0005">609884.0005</a>). The mutations consisted of 2 frameshift deletions, 2 splicing mutations, and a nonconservative missense change. The mutations were not found in over 120 ethnically matched normal control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16415887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Consugar, M. B., Kubly, V. J., Lager, D. J., Hommerding, C. J., Wong, W. C., Bakker, E., Gattone, V. H., II, Torres, V. E., Breuning, M. H., Harris, P. C. <strong>Molecular diagnostics of Meckel-Gruber syndrome highlights phenotypic differences between MKS1 and MKS3.</strong> Hum. Genet. 121: 591-599, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17377820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17377820</a>] [<a href="https://doi.org/10.1007/s00439-007-0341-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17377820">Consugar et al. (2007)</a> identified 7 novel pathogenic mutations in the TMEM67 gene (see, e.g., <a href="#0011">609884.0011</a>) in 5 of 17 families with a clinical diagnosis of Meckel syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17377820" 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>Joubert Syndrome 6</em></strong></p><p>
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Joubert syndrome (JBTS; see <a href="/entry/213300">213300</a>) is an autosomal recessive disorder characterized by cerebellar vermis hypoplasia associated with hypotonia, developmental delay, abnormal respiratory patterns, and abnormal eye movements. The association of retinal dystrophy and renal anomalies defines a subtype of JBTS. Occipital encephalocele and polydactyly have occasionally been reported in patients with JBTS. These features are also found in Meckel-Gruber syndrome. The phenotypic overlap between JBTS and Meckel-Gruber syndrome is supported by the central nervous system malformations seen in the Wpk rat model of Meckel-Gruber syndrome, which includes agenesis of the corpus callosum and hydrocephalus but not exencephaly. The missense mutation, P394L, seen in the rat Mks3 gene is presumably a hypomorphic allele because of the mild phenotype and viability of the Wpk rat (<a href="#17" class="mim-tip-reference" title="Smith, U. R., Consugar, M., Tee, L. J., McKee, B. M., Maina, E. N., Whelan, S., Morgan, N. V., Goranson, E., Gissen, P., Lilliquist, S., Aligianis, I. A., Ward, C. J., and 19 others. <strong>The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and wpk rat.</strong> Nature Genet. 38: 191-196, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16415887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16415887</a>] [<a href="https://doi.org/10.1038/ng1713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16415887">Smith et al., 2006</a>). While sequencing MKS1 (<a href="/entry/609883">609883</a>) and MKS3 genes in 31 unrelated fetuses presenting a cerebrorenodigital syndrome, which was designated 'Meckel-like' because of the absence of at least 1 of the MKS diagnostic criteria, <a href="#3" class="mim-tip-reference" title="Baala, L., Romano, S., Khaddour, R., Saunier, S., Smith, U. M., Audollent, S., Ozilou, C., Faivre, L., Laurent, N., Foliguet, B., Munnich, A., Lyonnet, S., and 9 others. <strong>The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome.</strong> Am. J. Hum. Genet. 80: 186-194, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17160906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17160906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17160906[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/510499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17160906">Baala et al. (2007)</a> identified MKS3 mutations in a family with 2 sibs. The pregnancies were terminated at 30 weeks' and 28 weeks' gestation, respectively, because of abnormal posterior fossae and hyperechogenic, enlarged kidneys detected by ultrasound. Kidney pathology in both fetuses showed liver bile duct proliferation and microcysts mainly in the medulla. Abnormalities in the brainstem resembling those of Joubert syndrome were described. The 2 sibs were found to be compound heterozygous for 2 mutations in the MKS3 gene: a missense mutation, Y513C, inherited from the father (<a href="#0006">609884.0006</a>) and an insertion/deletion mutation inherited from the mother (<a href="#0007">609884.0007</a>). Despite the absence of neurologic symptoms required for postnatal diagnosis in these sibs, <a href="#3" class="mim-tip-reference" title="Baala, L., Romano, S., Khaddour, R., Saunier, S., Smith, U. M., Audollent, S., Ozilou, C., Faivre, L., Laurent, N., Foliguet, B., Munnich, A., Lyonnet, S., and 9 others. <strong>The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome.</strong> Am. J. Hum. Genet. 80: 186-194, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17160906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17160906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17160906[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/510499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17160906">Baala et al. (2007)</a> questioned what MKS gene mutations could be found in patients with typical JBTS and sequenced 22 patients who had no deletion of the NPHP1 gene (<a href="/entry/607100">607100</a>). Sequence analysis revealed mutations in 3 patients. Studies identified the MKS3 gene as mutant in a sixth form of Joubert syndrome (JBTS6; <a href="/entry/610688">610688</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17160906+16415887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Otto, E. A., Tory, K., Attanasio, M., Zhou, W., Chaki, M., Paruchuri, Y., Wise, E. L., Wolf, M. T. F., Utsch, B., Becker, C., Nurnberg, G., Nurnberg, P., Nayir, A., Saunier, S., Antignac, C., Hildebrandt, F. <strong>Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).</strong> J. Med. Genet. 46: 663-670, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19508969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19508969</a>] [<a href="https://doi.org/10.1136/jmg.2009.066613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19508969">Otto et al. (2009)</a> identified TMEM67 mutations (see, e.g., <a href="#0011">609884.0011</a>; <a href="#0013">609884.0013</a>; <a href="#0019">609884.0019</a>; <a href="#0021">609884.0021</a>-<a href="#0023">609884.0023</a>) in 4 (3.3%) of 120 unrelated probands with Joubert syndrome. In 1 family another member was also affected. All 5 patients had ataxia, hypotonia or psychomotor retardation or showed cerebellar vermis hypo- or aplasia. All developed end-stage renal disease between 8 and 15 years of age, and 4 had hepatic fibrosis. Four also had ocular involvement, including blindness, retinal degeneration, or retinal coloboma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19508969" 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>Bardet-Biedl Syndrome</em></strong></p><p>
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The identification of mutations in the MKS1 gene (<a href="/entry/609883">609883</a>) in patients with clinical diagnoses of Bardet-Biedl syndrome (BBS; <a href="/entry/209900">209900</a>) led <a href="#14" class="mim-tip-reference" title="Leitch, C. C., Zaghloul, N. A., Davis, E. E., Stoetzel, C., Diaz-Font, A., Rix, S., Al-Fadhel, M., Lewis, R. A., Eyaid, W., Banin, E., Dollfus, H., Beales, P. L., Badano, J. L., Katsanis, N. <strong>Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome.</strong> Nature Genet. 40: 443-448, 2008. Note: Erratum: Nature Genet. 40: 927 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18327255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18327255</a>] [<a href="https://doi.org/10.1038/ng.97" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18327255">Leitch et al. (2008)</a> to investigate other Meckel syndrome genes as contributors to the BBS phenotype. While they did not find families with 2 pathogenic alleles in the MKS3 gene, they did find 2 families harboring potentially pathogenic heterozygous alleles. In one of these families a splice-site mutation in MKS3 was found with homozygosity for a BBS9 mutation (<a href="/entry/607968">607968</a>). An individual from the second family carried a complex allele encoding a protein with 2 in cis changes. One of the changes was predicted to be benign; the second, S320C (<a href="#0012">609884.0012</a>), was predicted to be pathogenic. This patient also carried a homozygous truncating mutation in CEP290 (<a href="/entry/610142#0013">610142.0013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18327255" 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>COACH Syndrome 1</em></strong></p><p>
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COACH syndrome-1 (COACH1; <a href="/entry/216360">216360</a>) is an autosomal recessive disorder originally described as including cerebellar vermis hypoplasia, oligophrenia, ataxia, ocular coloboma, and congenital hepatic fibrosis (<a href="#19" class="mim-tip-reference" title="Verloes, A., Lambotte, C. <strong>Further delineation of a syndrome of cerebellar vermis hypo/aplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis.</strong> Am. J. Med. Genet. 32: 227-232, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2929661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2929661</a>] [<a href="https://doi.org/10.1002/ajmg.1320320217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2929661">Verloes and Lambotte, 1989</a>). The clinical features overlap with those observed in Joubert and Meckel syndromes. In 8 (57%) of 14 families diagnosed with COACH syndrome, defined as Joubert syndrome with congenital liver fibrosis, <a href="#5" class="mim-tip-reference" title="Brancati, F., Iannicelli, M., Travaglini, L., Mazzotta, A., Bertini, E., Boltshauser, E., D'Arrigo, S., Emma, F., Fazzi, E., Gallizzi, R., Gentile, M., Loncarevic, D., and 12 others. <strong>MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement.</strong> Hum. Mutat. 30: E432-E442, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19058225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19058225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19058225[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.20924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19058225">Brancati et al. (2009)</a> identified compound heterozygous mutations in the TMEM67 gene (see, e.g., <a href="#0013">609884.0013</a>-<a href="/entry/609885#0016">609885.0016</a>). One of the families included the original family reported by <a href="#19" class="mim-tip-reference" title="Verloes, A., Lambotte, C. <strong>Further delineation of a syndrome of cerebellar vermis hypo/aplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis.</strong> Am. J. Med. Genet. 32: 227-232, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2929661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2929661</a>] [<a href="https://doi.org/10.1002/ajmg.1320320217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2929661">Verloes and Lambotte (1989)</a> (<a href="#0013">609884.0013</a> and <a href="#0014">609884.0014</a>). The phenotype in all patients was consistent with Joubert syndrome with congenital hepatic fibrosis, indicating that COACH syndrome can be considered a subtype of Joubert syndrome. The clinical variability of the disorder, relating to the extent and severity of liver and neurologic dysfunction as well as to the presence or absence of ocular and renal findings, was hypothesized to be due to genetic modifiers, similar to other ciliopathies, including Bardet-Biedl syndrome (BBS; <a href="/entry/209900">209900</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19058225+2929661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Doherty, D., Parisi, M. A., Finn, L. S., Gunay-Aygun, M., Al-Mateen, M., Bates, D., Clericuzio, C., Demir, H., Dorschner, M., van Essen, A. J., Gahl, W. A., Gentile, M., and 11 others. <strong>Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis).</strong> J. Med. Genet. 47: 8-21, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19574260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19574260</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19574260[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/10.1136/jmg.2009.067249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19574260">Doherty et al. (2010)</a> identified mutations in the TMEM67 gene in 19 (83%) of 23 families with COACH syndrome, defined as Joubert syndrome with liver disease. In contrast, TMEM67 mutations were only found in 2 (1%) of 209 families with Joubert syndrome without liver involvement. The findings further supported the concept that COACH syndrome is a form of Joubert syndrome with hepatic fibrosis. The proposed ciliary function for TMEM67 supported a unifying underlying pathophysiology for liver disease in these disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19574260" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 20-year-old Korean man with COACH syndrome, <a href="#13" class="mim-tip-reference" title="Lee, S.-H., Nam, T.-S., Li, W., Kim, J. H., Yoon, W., Choi, Y.-D., Kim, K.-H., Cai, H., Kim, M. J., Kim, C., Choy H. E., Kim, N., Chay, K. O., Kim, M.-K,, Choi, S.-Y. <strong>Functional validation of novel MKS3/TMEM67 mutations in COACH syndrome.</strong> Sci. Rep. 7: 10222, 2017. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28860541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28860541</a>] [<a href="https://doi.org/10.1038/s41598-017-10652-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28860541">Lee et al. (2017)</a> identified compound heterozygous mutations in the TMEM67 gene (G132A, <a href="#0027">609884.0027</a> and c.2758delT, <a href="#0028">609884.0028</a>). Transfection experiments in HEK293T cells showed that the c.2758delT mutation resulted in decreased stability and increased turnover of the protein, and the G132A mutation resulted in decreased mRNA expression, compared to wildtype. In TMEM67 knockdown zebrafish with a hydrocephalus phenotype, injection with mutant morpholinos containing the G132A or c.2758delT mutation did not rescue the phenotype. Injection with the 2 mutant morpholinos in the TMEM67 knockdown zebrafish also did not rescue wnt signaling defects, as evidenced by suppressed axin2 (<a href="/entry/604025">604025</a>) mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28860541" 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>Nephronophthisis 11</em></strong></p><p>
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In patients with nephronophthisis and hepatic fibrosis (NPHP11; <a href="/entry/613550">613550</a>), <a href="#15" class="mim-tip-reference" title="Otto, E. A., Tory, K., Attanasio, M., Zhou, W., Chaki, M., Paruchuri, Y., Wise, E. L., Wolf, M. T. F., Utsch, B., Becker, C., Nurnberg, G., Nurnberg, P., Nayir, A., Saunier, S., Antignac, C., Hildebrandt, F. <strong>Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).</strong> J. Med. Genet. 46: 663-670, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19508969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19508969</a>] [<a href="https://doi.org/10.1136/jmg.2009.066613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19508969">Otto et al. (2009)</a> identified homozygous or compound heterozygous missense mutations in the TMEM67 gene (see, e.g., <a href="#0018">609884.0018</a>-<a href="#0021">609884.0021</a>). Mutations in the TMEM67 gene were not found in 105 NPHP patients without liver fibrosis, suggesting that liver fibrosis is a specific feature of TMEM67 mutations. <a href="#15" class="mim-tip-reference" title="Otto, E. A., Tory, K., Attanasio, M., Zhou, W., Chaki, M., Paruchuri, Y., Wise, E. L., Wolf, M. T. F., Utsch, B., Becker, C., Nurnberg, G., Nurnberg, P., Nayir, A., Saunier, S., Antignac, C., Hildebrandt, F. <strong>Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).</strong> J. Med. Genet. 46: 663-670, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19508969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19508969</a>] [<a href="https://doi.org/10.1136/jmg.2009.066613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19508969">Otto et al. (2009)</a> concluded that mutations in TMEM67 can cause NPHP in patients with additional liver fibrosis but without neurologic involvement and with normal brain imaging, and that NPHP11, MKS3, and JBTS6 represent a spectrum of allelic disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19508969" 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>RHYNS Syndrome</em></strong></p><p>
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In a 38-year-old Italian man with RHYNS syndrome (RHYNS; <a href="/entry/602152">602152</a>), <a href="#4" class="mim-tip-reference" title="Brancati, F., Camerota, L., Colao, E., Vega-Warner, V., Zhao, X., Zhang, R., Bottillo, I., Castori, M., Caglioti, A., Sangiuolo, F., Novelli, G., Perrotti, N., and 16 others. <strong>Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome.</strong> Europ. J. Hum. Genet. 26: 1266-1271, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29891882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29891882</a>] [<a href="https://doi.org/10.1038/s41431-018-0183-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29891882">Brancati et al. (2018)</a> identified compound heterozygosity for a nonsense mutation (R208X; <a href="#0011">609884.0011</a>) and a missense mutation (D430G; <a href="#0026">609884.0026</a>) in the TMEM67 gene. The mutations segregated with disease in the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29891882" 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="#15" class="mim-tip-reference" title="Otto, E. A., Tory, K., Attanasio, M., Zhou, W., Chaki, M., Paruchuri, Y., Wise, E. L., Wolf, M. T. F., Utsch, B., Becker, C., Nurnberg, G., Nurnberg, P., Nayir, A., Saunier, S., Antignac, C., Hildebrandt, F. <strong>Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).</strong> J. Med. Genet. 46: 663-670, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19508969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19508969</a>] [<a href="https://doi.org/10.1136/jmg.2009.066613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19508969">Otto et al. (2009)</a> found homozygosity or compound heterozygosity for missense mutations in the TMEM67 gene (<a href="#0018">609884.0018</a>-<a href="#0021">609884.0021</a>) in patients with NPHP11 and hepatic fibrosis. All patients with NPHP and hepatic fibrosis and no brain anomaly carried a missense mutation affecting either amino acid C615 or G821. Thus, <a href="#15" class="mim-tip-reference" title="Otto, E. A., Tory, K., Attanasio, M., Zhou, W., Chaki, M., Paruchuri, Y., Wise, E. L., Wolf, M. T. F., Utsch, B., Becker, C., Nurnberg, G., Nurnberg, P., Nayir, A., Saunier, S., Antignac, C., Hildebrandt, F. <strong>Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).</strong> J. Med. Genet. 46: 663-670, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19508969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19508969</a>] [<a href="https://doi.org/10.1136/jmg.2009.066613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19508969">Otto et al. (2009)</a> suggested that some hypomorphic mutations of TMEM67 do not lead to any neurologic impairment. Four additional patients with a more severe phenotype of Joubert syndrome-6 also had homozygous or compound heterozygous mutations (see, e.g., <a href="#0011">609884.0011</a>; <a href="#0013">609884.0013</a>; <a href="#0019">609884.0019</a>; <a href="#0021">609884.0021</a>-<a href="#0023">609884.0023</a>). None of the patients with JBTS6 had truncating mutations on both alleles; all had at least 1 missense allele. Finally, the liver seems to be affected in most of the patients with TMEM67 mutations independently of the neurologic involvement, suggesting that liver disease is a specific feature resulting from TMEM67 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19508969" 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 the Wistar polycystic kidneys (Wpk) rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum, and hydrocephalus, <a href="#17" class="mim-tip-reference" title="Smith, U. R., Consugar, M., Tee, L. J., McKee, B. M., Maina, E. N., Whelan, S., Morgan, N. V., Goranson, E., Gissen, P., Lilliquist, S., Aligianis, I. A., Ward, C. J., and 19 others. <strong>The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and wpk rat.</strong> Nature Genet. 38: 191-196, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16415887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16415887</a>] [<a href="https://doi.org/10.1038/ng1713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16415887">Smith et al. (2006)</a> refined the mapping of the Wpk locus and identified a missense mutation in the rat Tmem67 gene that was not present in the parental Wistar strain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16415887" 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 the Wpk rat model of MKS3, <a href="#18" class="mim-tip-reference" title="Tammachote, R., Hommerding, C. J., Sinders, R. M., Miller, C. A., Czarnecki, P. G., Leightner, A. C., Salisbury, J. L., Ward, C. J., Torres, V. E., Gattone, V. H., II, Harris, P. C. <strong>Ciliary and centrosomal defects associated with mutation and depletion of the Meckel syndrome genes MKS1 and MKS3.</strong> Hum. Molec. Genet. 18: 3311-3323, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19515853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19515853</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19515853[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19515853">Tammachote et al. (2009)</a> reported functional defects of the connecting cilium in the eye that resulted in lack of formation of the outer segment, whereas infertile Wpk males developed spermatids with very short flagella that did not extend beyond the cell body. In Wpk renal collecting duct cysts, cilia were generally longer than normal, with additional evidence of cells with multiple primary cilia and centrosome overduplication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19515853" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Garcia-Gonzalo, F. R., Corbit, K. C., Sirerol-Piquer, M. S., Ramaswami, G., Otto, E. A., Noriega, T. R., Seol, A. D., Robinson, J. F., Bennett, C. L., Josifova, D. J., Garcia-Verdugo, J. M., Katsanis, N., Hildebrandt, F., Reiter, J. F. <strong>A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition.</strong> Nature Genet. 43: 776-784, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21725307/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21725307</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21725307[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.891" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21725307">Garcia-Gonzalo et al. (2011)</a> found that Tmem67-null mice survived to birth without overt morphologic abnormalities, but died soon after. By embryonic day 18.5, Tmem67-null embryonic kidneys had developed cysts, and kidney tubules had fewer cilia than controls. Tmem67-null embryonic fibroblasts did not have ciliary defects, suggesting that Tmem67 has tissue-specific roles in ciliogenesis. <a href="#11" class="mim-tip-reference" title="Garcia-Gonzalo, F. R., Corbit, K. C., Sirerol-Piquer, M. S., Ramaswami, G., Otto, E. A., Noriega, T. R., Seol, A. D., Robinson, J. F., Bennett, C. L., Josifova, D. J., Garcia-Verdugo, J. M., Katsanis, N., Hildebrandt, F., Reiter, J. F. <strong>A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition.</strong> Nature Genet. 43: 776-784, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21725307/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21725307</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21725307[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.891" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21725307">Garcia-Gonzalo et al. (2011)</a> also demonstrated that Tmem67 interacts with Tctn1 (<a href="/entry/609863">609863</a>) and Tctn2 (<a href="/entry/613846">613846</a>) and other proteins in a large complex localized to the transition zone between the ciliary axoneme and the basal body. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21725307" 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="Adams, M., Simms, R. J., Abdelhamed, Z., Dawe, H. R., Szymanska, K., Logan, C. V., Wheway, G., Pitt, E., Gull, K., Knowles, M. A., Blair, E., Cross, S. H., Sayer, J. A., Johnson, C. A. <strong>A meckelin-filamin A interaction mediates ciliogenesis.</strong> Hum. Molec. Genet. 21: 1272-1286, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22121117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22121117</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22121117[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddr557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22121117">Adams et al. (2012)</a> found that knockdown of Mks3 or the Flna ortholog in zebrafish resulted in similar phenotypes, including brain and body axis defects, cardiac edema, and otic placode and eye defects. Combined low doses of both Mks3 and Flna morpholinos increased both the incidence and severity of developmental defects. An Flna-null mouse strain showed similar defects. At embryonic day 13.5, male Flna hemizygous embryos were highly dysmorphic, with extensive disruption of ventricular zone of the neocortex and severe periventricular heterotopia. Basal body position was disrupted and neuroepithelial layer showed impaired ciliogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22121117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Abdelhamed, Z. A., Wheway, G., Szymanska, K., Natarajan, S., Toomes, C., Inglehearn, C., Johnson, C. A. <strong>Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects.</strong> Hum. Molec. Genet. 22: 1358-1372, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23283079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23283079</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23283079[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/dds546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23283079">Abdelhamed et al. (2013)</a> found that knockdown of Tmem67 in mice recapitulated the phenotypic variability of neurologic features seen in human ciliopathies. Two main phenotypic groups were recognized. Incipient congenic mice (F6 to F10) showed MKS-like features with variable neurologic abnormalities, including exencephaly and frontal/occipital encephalocele associated with the loss of primary cilia, diminished Shh signaling, and dorsalization of the caudal neural tube. These mutant mice also showed highly deregulated canonical Wnt/beta-catenin (CTNNB1; <a href="/entry/116806">116806</a>) signaling associated with hyperactive DVL1 (<a href="/entry/601365">601365</a>) localized to the basal body: DVL1 is the downstream signaling modulator of Wnt pathways. Conversely, fully congenic mice (F greater than 10) had less variable neurodevelopmental features that were characteristic of JBTS, including cerebellar hypoplasia consistent with the molar tooth sign on imaging, and retention of abnormal bulbous cilia associated with neural tube ventralization. These mutant mice had low levels of deregulated canonical Wnt signaling associated with the loss of DVL1 localization to the basal body. <a href="#1" class="mim-tip-reference" title="Abdelhamed, Z. A., Wheway, G., Szymanska, K., Natarajan, S., Toomes, C., Inglehearn, C., Johnson, C. A. <strong>Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects.</strong> Hum. Molec. Genet. 22: 1358-1372, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23283079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23283079</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23283079[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/dds546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23283079">Abdelhamed et al. (2013)</a> suggested that modifier alleles likely determine the variation between MKS and JBTS caused by TMEM67 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23283079" 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">rs386834200 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386834200;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=rs386834200" 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=rs386834200" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an individual with Meckel syndrome type 3 (MKS3; <a href="/entry/607361">607361</a>) from Oman, <a href="#17" class="mim-tip-reference" title="Smith, U. R., Consugar, M., Tee, L. J., McKee, B. M., Maina, E. N., Whelan, S., Morgan, N. V., Goranson, E., Gissen, P., Lilliquist, S., Aligianis, I. A., Ward, C. J., and 19 others. <strong>The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and wpk rat.</strong> Nature Genet. 38: 191-196, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16415887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16415887</a>] [<a href="https://doi.org/10.1038/ng1713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16415887">Smith et al. (2006)</a> found a homozygous 2-bp deletion in exon 3 of the MKS3 gene, 383_384delAC, causing a frameshift beginning at his128 with premature stop at residue 140 (H128fsTer140). Each of the first-cousin parents was heterozygous for the mutation. The affected individual had occipital encephalocele, Dandy-Walker cysts, renal cystic dysplasia, hepatic developmental defects, and left-hand postaxial polydactyly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16415887" 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">rs386834204 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386834204;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=rs386834204" 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=rs386834204" 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=RCV000001431" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001431" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001431</a>
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<p>In a Pakistani family with Meckel syndrome type 3 (MKS3; <a href="/entry/607361">607361</a>), <a href="#17" class="mim-tip-reference" title="Smith, U. R., Consugar, M., Tee, L. J., McKee, B. M., Maina, E. N., Whelan, S., Morgan, N. V., Goranson, E., Gissen, P., Lilliquist, S., Aligianis, I. A., Ward, C. J., and 19 others. <strong>The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and wpk rat.</strong> Nature Genet. 38: 191-196, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16415887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16415887</a>] [<a href="https://doi.org/10.1038/ng1713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16415887">Smith et al. (2006)</a> found that 2 affected sibs carried a homozygous 1-bp deletion (647delA) in exon 6 of the MKS3 gene. The deletion caused a frameshift beginning at glu216 of the protein, with premature termination at residue 221. The sibs had occipital encephalocele, renal cystic dysplasia, hepatic developmental defects, and midline cleft palate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16415887" 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 immunohistochemical analysis, <a href="#8" class="mim-tip-reference" title="Dawe, H. R., Smith, U. M., Cullinane, A. R., Gerrelli, D., Cox, P., Badano, J. L., Blair-Reid, S., Sriram, N., Katsanis, N., Attie-Bitach, T., Afford, S. C., Copp, A. J., Kelly, D. A., Gull, K., Johnson, C. A. <strong>The Meckel-Gruber syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation.</strong> Hum. Molec. Genet. 16: 173-186, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17185389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17185389</a>] [<a href="https://doi.org/10.1093/hmg/ddl459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17185389">Dawe et al. (2007)</a> found complete lack of meckelin expression in kidney from a patient with the 647delA mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17185389" 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">rs386834207 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386834207;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=rs386834207" 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=rs386834207" 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=RCV000001432" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001432" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001432</a>
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<p>In a Pakistani family with Meckel syndrome type 3 (MKS3; <a href="/entry/607361">607361</a>), <a href="#17" class="mim-tip-reference" title="Smith, U. R., Consugar, M., Tee, L. J., McKee, B. M., Maina, E. N., Whelan, S., Morgan, N. V., Goranson, E., Gissen, P., Lilliquist, S., Aligianis, I. A., Ward, C. J., and 19 others. <strong>The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and wpk rat.</strong> Nature Genet. 38: 191-196, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16415887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16415887</a>] [<a href="https://doi.org/10.1038/ng1713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16415887">Smith et al. (2006)</a> found that a child with Meckel syndrome carried a homozygous splice site mutation, IVS8-2A-G, in the MKS3 gene. The child had occipital encephalocele, renal cystic dysplasia, and hepatic developmental defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16415887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 MECKEL SYNDROME, TYPE 3</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137853106 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853106;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=rs137853106" 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=rs137853106" 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=RCV000001434" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001434" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001434</a>
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<p>In a Pakistani patient with Meckel syndrome type 3 (MKS3; <a href="/entry/607361">607361</a>), <a href="#17" class="mim-tip-reference" title="Smith, U. R., Consugar, M., Tee, L. J., McKee, B. M., Maina, E. N., Whelan, S., Morgan, N. V., Goranson, E., Gissen, P., Lilliquist, S., Aligianis, I. A., Ward, C. J., and 19 others. <strong>The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and wpk rat.</strong> Nature Genet. 38: 191-196, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16415887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16415887</a>] [<a href="https://doi.org/10.1038/ng1713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16415887">Smith et al. (2006)</a> found a homozygous 1127A-C transversion in exon 11 of the MKS3 gene causing a missense protein change, Q376P. The patient had occipital encephalocele, renal cystic dysplasia, hepatic developmental defects, midline cleft palate, and epididymal cysts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16415887" 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 immunohistochemical analysis, <a href="#8" class="mim-tip-reference" title="Dawe, H. R., Smith, U. M., Cullinane, A. R., Gerrelli, D., Cox, P., Badano, J. L., Blair-Reid, S., Sriram, N., Katsanis, N., Attie-Bitach, T., Afford, S. C., Copp, A. J., Kelly, D. A., Gull, K., Johnson, C. A. <strong>The Meckel-Gruber syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation.</strong> Hum. Molec. Genet. 16: 173-186, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17185389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17185389</a>] [<a href="https://doi.org/10.1093/hmg/ddl459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17185389">Dawe et al. (2007)</a> found that the Q376P substitution in the N-terminal extracellular domain of meckelin resulted in lack of meckelin at the cell surface due to accumulation of the mutant protein in the endoplasmic reticulum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17185389" 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">rs386834187 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386834187;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=rs386834187" 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=rs386834187" 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 Pakistani cases of Meckel syndrome type 3 (MKS3; <a href="/entry/607361">607361</a>) in individuals related as double first cousins, <a href="#17" class="mim-tip-reference" title="Smith, U. R., Consugar, M., Tee, L. J., McKee, B. M., Maina, E. N., Whelan, S., Morgan, N. V., Goranson, E., Gissen, P., Lilliquist, S., Aligianis, I. A., Ward, C. J., and 19 others. <strong>The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and wpk rat.</strong> Nature Genet. 38: 191-196, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16415887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16415887</a>] [<a href="https://doi.org/10.1038/ng1713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16415887">Smith et al. (2006)</a> found that the disorder was related to a homozygous splice site mutation in intron 15 of the MKS3 gene: IVS15+1G-A. One patient had occipital encephalocele, renal cystic dysplasia, and hepatic developmental defects; the other had the same 3 features as well as bilateral postaxial polydactyly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16415887" 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>.0006 JOUBERT SYNDROME 6</strong>
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COACH SYNDROME 1, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137853107 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853107;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/rs137853107?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=rs137853107" 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=rs137853107" 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=RCV000001436 OR RCV000001437 OR RCV001851544 OR RCV004585980 OR RCV005049307" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001436, RCV000001437, RCV001851544, RCV004585980, RCV005049307" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001436...</a>
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<p><strong><em>Joubert Syndrome 6</em></strong></p><p>
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In 2 sibs derived from pregnancies terminated at 30 weeks' and 28 weeks' gestation, respectively, because of abnormal posterior fossae and hyperechogenic, enlarged kidneys detected by ultrasound, <a href="#3" class="mim-tip-reference" title="Baala, L., Romano, S., Khaddour, R., Saunier, S., Smith, U. M., Audollent, S., Ozilou, C., Faivre, L., Laurent, N., Foliguet, B., Munnich, A., Lyonnet, S., and 9 others. <strong>The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome.</strong> Am. J. Hum. Genet. 80: 186-194, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17160906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17160906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17160906[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/510499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17160906">Baala et al. (2007)</a> found compound heterozygosity for 2 mutations in the MKS3 gene. A missense mutation in exon 15, tyr513 to cys (Y513C), was inherited from the father; a complex indel mutation (13-bp deletion encompassing the exon 22/intron 22 boundary replaced by 2 bp) was inherited from the mother. This 2315_2323+4del13insGG mutation (<a href="#0007">609884.0007</a>) removed the donor splice site. Strong suspicion of Joubert syndrome in this family prompted a search for MKS3 mutations in patients with a typical form of the disorder and led to the establishment of a sixth locus for Joubert syndrome (JBTS6; <a href="/entry/610688">610688</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17160906" 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>COACH Syndrome 1</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="Doherty, D., Parisi, M. A., Finn, L. S., Gunay-Aygun, M., Al-Mateen, M., Bates, D., Clericuzio, C., Demir, H., Dorschner, M., van Essen, A. J., Gahl, W. A., Gentile, M., and 11 others. <strong>Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis).</strong> J. Med. Genet. 47: 8-21, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19574260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19574260</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19574260[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/10.1136/jmg.2009.067249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19574260">Doherty et al. (2010)</a> identified the Y513C mutation in compound heterozygosity with another pathogenic TMEM67 mutation (see, e.g., I833T, <a href="#0013">609884.0013</a>) in 2 families with COACH syndrome-1 (COACH1; <a href="/entry/216360">216360</a>), defined as Joubert syndrome with hepatic involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19574260" 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 JOUBERT SYNDROME 6</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1554557920 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554557920;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=rs1554557920" 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=rs1554557920" 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=RCV000001433" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001433" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001433</a>
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<p>For discussion of the complex indel mutation in the TMEM67 gene (13-bp deletion encompassing the exon 22/intron 22 boundary replaced by 2 bp) that was found in compound heterozygous state in a patient with Joubert syndrome-6 (JBTS6; <a href="/entry/610688">610688</a>) by <a href="#3" class="mim-tip-reference" title="Baala, L., Romano, S., Khaddour, R., Saunier, S., Smith, U. M., Audollent, S., Ozilou, C., Faivre, L., Laurent, N., Foliguet, B., Munnich, A., Lyonnet, S., and 9 others. <strong>The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome.</strong> Am. J. Hum. Genet. 80: 186-194, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17160906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17160906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17160906[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/510499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17160906">Baala et al. (2007)</a>, see <a href="#0006">609884.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17160906" 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 id="0008" class="mim-anchor"></a>
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<strong>.0008 JOUBERT SYNDROME 6</strong>
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TMEM67, IVS23+5G-C
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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> rs756686115 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs756686115;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/rs756686115?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=rs756686115" 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=rs756686115" 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=RCV000001438 OR RCV002512641" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001438, RCV002512641" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001438...</a>
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<p>In a 14-year-old Algerian girl, the child of consanguineous parents, with the molar tooth sign and superior vermian dysplasia (JBTS6; <a href="/entry/610688">610688</a>), <a href="#3" class="mim-tip-reference" title="Baala, L., Romano, S., Khaddour, R., Saunier, S., Smith, U. M., Audollent, S., Ozilou, C., Faivre, L., Laurent, N., Foliguet, B., Munnich, A., Lyonnet, S., and 9 others. <strong>The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome.</strong> Am. J. Hum. Genet. 80: 186-194, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17160906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17160906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17160906[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/510499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17160906">Baala et al. (2007)</a> found homozygous MKS3 mutation near the donor splice site of intron 23 (IVS23+5G-C). Both parents and a healthy sister were heterozygous for the mutation. Sequencing of RNA transcript confirmed exon skipping from exons 22 to 24. This in-frame deletion predicted a protein lacking amino acids 775 to 813, which compose most of the putative coiled-coil domain of the protein. This patient had been reported by <a href="#16" class="mim-tip-reference" title="Romano, S., Boddaert, N., Desguerre, I., Hubert, L., Salomon, R., Seidenwurm, D., Bahi-Buisson, N., Nabbout, R., Sonigo, P., Lyonnet, S., Brunelle, F., Munnich, A., de Lonlay, P. <strong>Molar tooth sign and superior vermian dysplasia: a radiological, clinical, and genetic study.</strong> Neuropediatrics 37: 42-45, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16541367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16541367</a>] [<a href="https://doi.org/10.1055/s-2006-923838" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16541367">Romano et al. (2006)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16541367+17160906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 JOUBERT SYNDROME 6</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs199821258 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199821258;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/rs199821258?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=rs199821258" 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=rs199821258" 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=RCV000001439 OR RCV000050199 OR RCV001698938 OR RCV001851545 OR RCV002281687 OR RCV004732520" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001439, RCV000050199, RCV001698938, RCV001851545, RCV002281687, RCV004732520" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001439...</a>
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<p><a href="#3" class="mim-tip-reference" title="Baala, L., Romano, S., Khaddour, R., Saunier, S., Smith, U. M., Audollent, S., Ozilou, C., Faivre, L., Laurent, N., Foliguet, B., Munnich, A., Lyonnet, S., and 9 others. <strong>The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome.</strong> Am. J. Hum. Genet. 80: 186-194, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17160906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17160906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17160906[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/510499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17160906">Baala et al. (2007)</a> demonstrated compound heterozygosity for mutations in the MKS3 gene in a 7-year-old girl with a mild form of Joubert syndrome (JBTS6; <a href="/entry/610688">610688</a>). The patient had been reported by <a href="#16" class="mim-tip-reference" title="Romano, S., Boddaert, N., Desguerre, I., Hubert, L., Salomon, R., Seidenwurm, D., Bahi-Buisson, N., Nabbout, R., Sonigo, P., Lyonnet, S., Brunelle, F., Munnich, A., de Lonlay, P. <strong>Molar tooth sign and superior vermian dysplasia: a radiological, clinical, and genetic study.</strong> Neuropediatrics 37: 42-45, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16541367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16541367</a>] [<a href="https://doi.org/10.1055/s-2006-923838" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16541367">Romano et al. (2006)</a>. Three MKS3 variations were found: on the maternal allele, a donor splice site mutation in intron 6 (IVS6+2T-G), and on the paternal allele, a missense mutation located in exon 16 (G545E; <a href="#0010">609884.0010</a>) and a mutation located at the last base of exon 21 (2341G-A; <a href="#0010">609884.0010</a>). Either of the mutations from the father could be deleterious. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16541367+17160906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 JOUBERT SYNDROME 6</strong>
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TMEM67, GLY545GLU AND 2341G-A
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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> rs115563233 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs115563233;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/rs115563233?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=rs115563233" 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=rs115563233" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <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> rs267607114 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607114;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/rs267607114?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=rs267607114" 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=rs267607114" 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=RCV000234818 OR RCV000723708 OR RCV001087450 OR RCV001163248 OR RCV001163249 OR RCV001163250 OR RCV002294093 OR RCV002512642 OR RCV003388643 OR RCV004732810 OR RCV004808544" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000234818, RCV000723708, RCV001087450, RCV001163248, RCV001163249, RCV001163250, RCV002294093, RCV002512642, RCV003388643, RCV004732810, RCV004808544" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000234818...</a>
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<p>For discussion of the in cis gly545-to-glu (G545E) and 2431G-A mutations in the TMEM67 gene that were found in compound heterozygous state in a patient with Joubert syndrome-6 (JBTS6; <a href="/entry/610688">610688</a>) by <a href="#3" class="mim-tip-reference" title="Baala, L., Romano, S., Khaddour, R., Saunier, S., Smith, U. M., Audollent, S., Ozilou, C., Faivre, L., Laurent, N., Foliguet, B., Munnich, A., Lyonnet, S., and 9 others. <strong>The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome.</strong> Am. J. Hum. Genet. 80: 186-194, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17160906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17160906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17160906[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/510499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17160906">Baala et al. (2007)</a>, see <a href="#0009">609884.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17160906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 MECKEL SYNDROME, TYPE 3</strong>
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JOUBERT SYNDROME 6, INCLUDED<br />
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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> rs137853108 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853108;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/rs137853108?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=rs137853108" 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=rs137853108" 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=RCV000001442 OR RCV000001443 OR RCV000334857 OR RCV000468558 OR RCV000494327 OR RCV000723362 OR RCV002298428 OR RCV002490291 OR RCV003242959" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001442, RCV000001443, RCV000334857, RCV000468558, RCV000494327, RCV000723362, RCV002298428, RCV002490291, RCV003242959" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001442...</a>
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<p><strong><em>Meckel Syndrome 3</em></strong></p><p>
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In affected fetuses from 3 unrelated families with Meckel syndrome type 3 (MKS3; <a href="/entry/607361">607361</a>), <a href="#6" class="mim-tip-reference" title="Consugar, M. B., Kubly, V. J., Lager, D. J., Hommerding, C. J., Wong, W. C., Bakker, E., Gattone, V. H., II, Torres, V. E., Breuning, M. H., Harris, P. C. <strong>Molecular diagnostics of Meckel-Gruber syndrome highlights phenotypic differences between MKS1 and MKS3.</strong> Hum. Genet. 121: 591-599, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17377820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17377820</a>] [<a href="https://doi.org/10.1007/s00439-007-0341-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17377820">Consugar et al. (2007)</a> identified a heterozygous 622A-T transversion in exon 6 of the TMEM67 gene, resulting in an arg208-to-ter (R208X) substitution. All fetuses were compound heterozygous for R208X and another pathogenic mutation in the TMEM67 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17377820" 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>Joubert Syndrome 6</em></strong></p><p>
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In a German patient with Joubert syndrome-6 (JBTS6; <a href="/entry/610688">610688</a>), <a href="#15" class="mim-tip-reference" title="Otto, E. A., Tory, K., Attanasio, M., Zhou, W., Chaki, M., Paruchuri, Y., Wise, E. L., Wolf, M. T. F., Utsch, B., Becker, C., Nurnberg, G., Nurnberg, P., Nayir, A., Saunier, S., Antignac, C., Hildebrandt, F. <strong>Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).</strong> J. Med. Genet. 46: 663-670, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19508969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19508969</a>] [<a href="https://doi.org/10.1136/jmg.2009.066613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19508969">Otto et al. (2009)</a> identified compound heterozygosity for 2 mutations in the TMEM67 gene: R208X and I833T (<a href="#0013">609884.0013</a>). The patient had end-stage renal failure at age 15, hepatic fibrosis, mental retardation, and cerebellar vermis atrophy. No ocular involvement was observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19508969" 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>RHYNS Syndrome</em></strong></p><p>
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In a 38-year-old Italian man with RHYNS syndrome (RHYNS; <a href="/entry/602152">602152</a>), originally reported by <a href="#9" class="mim-tip-reference" title="Di Rocco, M., Picco, P., Arslanian, A., Restagno, G., Perfumo, F., Buoncompagni, A., Gattorno, M., Borrone, C. <strong>Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): a new syndrome?</strong> Am. J. Med. Genet. 73: 1-4, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9375913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9375913</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19971128)73:1<1::aid-ajmg1>3.0.co;2-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9375913">Di Rocco et al. (1997)</a>, <a href="#4" class="mim-tip-reference" title="Brancati, F., Camerota, L., Colao, E., Vega-Warner, V., Zhao, X., Zhang, R., Bottillo, I., Castori, M., Caglioti, A., Sangiuolo, F., Novelli, G., Perrotti, N., and 16 others. <strong>Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome.</strong> Europ. J. Hum. Genet. 26: 1266-1271, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29891882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29891882</a>] [<a href="https://doi.org/10.1038/s41431-018-0183-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29891882">Brancati et al. (2018)</a> identified compound heterozygosity for the R208X mutation (c.622A-T, NM_153704.5) in the TMEM67 gene, and a c.1289A-G transition in exon 13, resulting in an asp430-to-gly (D430G; <a href="#0026">609884.0026</a>) substitution. His unaffected father and 2 unaffected brothers were heterozygous for the nonsense mutation, and his unaffected mother was heterozygous for the missense mutation. The D430G missense mutation was not found in the 1000 Genomes Project, ExAC, or gnomAD databases, whereas the nonsense mutation was present at very low frequency in the gnomAD database (49 of 277,178 alleles). Minigene assay using the pSPL3 vector system revealed absence of exon 13 after transfection with the D430G mutant; the authors suggested that the c.1289A-G mutation might result in exon 13 skipping, causing a frameshift and premature termination (Asp430SerfsTer9). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9375913+29891882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 BARDET-BIEDL SYNDROME 14, MODIFIER OF</strong>
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TMEM67, SER320CYS
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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> rs111619594 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111619594;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/rs111619594?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=rs111619594" 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=rs111619594" 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=RCV000001444 OR RCV000234830 OR RCV000725926 OR RCV001085857 OR RCV001158404 OR RCV001158405 OR RCV001158406 OR RCV001198570 OR RCV001333012 OR RCV003488318 OR RCV004528064" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001444, RCV000234830, RCV000725926, RCV001085857, RCV001158404, RCV001158405, RCV001158406, RCV001198570, RCV001333012, RCV003488318, RCV004528064" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001444...</a>
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<p>In an 11-year-old female patient with Bardet-Biedl syndrome (see BBS14, <a href="/entry/615991">615991</a>) <a href="#14" class="mim-tip-reference" title="Leitch, C. C., Zaghloul, N. A., Davis, E. E., Stoetzel, C., Diaz-Font, A., Rix, S., Al-Fadhel, M., Lewis, R. A., Eyaid, W., Banin, E., Dollfus, H., Beales, P. L., Badano, J. L., Katsanis, N. <strong>Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome.</strong> Nature Genet. 40: 443-448, 2008. Note: Erratum: Nature Genet. 40: 927 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18327255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18327255</a>] [<a href="https://doi.org/10.1038/ng.97" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18327255">Leitch et al. (2008)</a> found heterozygosity for a complex mutation in the TMEM67 gene coding for a protein with 2 in cis changes, in addition to homozygosity for a truncating mutation of the CEP290 gene (<a href="/entry/610142#0013">610142.0013</a>). One of the substitutions in the TMEM67 gene was predicted computationally to be benign, while the other, ser320 to cys (S320C), occurred at a highly conserved residue and was predicted to be pathogenic. The S320C mutation resulted in severe gastrulation movement defects in zebrafish embryos. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18327255" 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> rs267607119 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607119;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/rs267607119?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=rs267607119" 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=rs267607119" 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=RCV000001445 OR RCV000001446 OR RCV000821785 OR RCV000995902 OR RCV001310635 OR RCV001536092 OR RCV001804708 OR RCV003315221" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001445, RCV000001446, RCV000821785, RCV000995902, RCV001310635, RCV001536092, RCV001804708, RCV003315221" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001445...</a>
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<p><strong><em>COACH Syndrome 1</em></strong></p><p>
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In 2 sibs originally reported by <a href="#19" class="mim-tip-reference" title="Verloes, A., Lambotte, C. <strong>Further delineation of a syndrome of cerebellar vermis hypo/aplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis.</strong> Am. J. Med. Genet. 32: 227-232, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2929661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2929661</a>] [<a href="https://doi.org/10.1002/ajmg.1320320217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2929661">Verloes and Lambotte (1989)</a> as having COACH syndrome (COACH1; <a href="/entry/216360">216360</a>), <a href="#5" class="mim-tip-reference" title="Brancati, F., Iannicelli, M., Travaglini, L., Mazzotta, A., Bertini, E., Boltshauser, E., D'Arrigo, S., Emma, F., Fazzi, E., Gallizzi, R., Gentile, M., Loncarevic, D., and 12 others. <strong>MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement.</strong> Hum. Mutat. 30: E432-E442, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19058225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19058225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19058225[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.20924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19058225">Brancati et al. (2009)</a> identified compound heterozygosity for 2 mutations in the TMEM67 gene: a 2498T-C transition in exon 24, resulting in an ile833-to-thr (I833T) substitution, and a splice site mutation in intron 24 (2556+1G-T; <a href="#0014">609884.0014</a>). An unrelated patient from Croatia was compound heterozygous for I833T and another splice site mutation in intron 2 (312+5G-A; <a href="#0015">609884.0015</a>). The phenotype in all patients was consistent with Joubert syndrome (JBTS6; <a href="/entry/610688">610688</a>) with congenital hepatic fibrosis, indicating that COACH syndrome is a subtype of Joubert syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19058225+2929661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Doherty, D., Parisi, M. A., Finn, L. S., Gunay-Aygun, M., Al-Mateen, M., Bates, D., Clericuzio, C., Demir, H., Dorschner, M., van Essen, A. J., Gahl, W. A., Gentile, M., and 11 others. <strong>Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis).</strong> J. Med. Genet. 47: 8-21, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19574260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19574260</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19574260[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/10.1136/jmg.2009.067249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19574260">Doherty et al. (2010)</a> identified the I833T mutation in compound heterozygosity with another pathogenic TMEM67 mutation (see, e.g., Y513C; <a href="#0006">609884.0006</a>) in 4 unrelated patients with COACH syndrome, which the authors defined as Joubert syndrome with liver involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19574260" 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>Joubert Syndrome 6</em></strong></p><p>
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In a patient diagnosed with Joubert syndrome, <a href="#15" class="mim-tip-reference" title="Otto, E. A., Tory, K., Attanasio, M., Zhou, W., Chaki, M., Paruchuri, Y., Wise, E. L., Wolf, M. T. F., Utsch, B., Becker, C., Nurnberg, G., Nurnberg, P., Nayir, A., Saunier, S., Antignac, C., Hildebrandt, F. <strong>Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).</strong> J. Med. Genet. 46: 663-670, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19508969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19508969</a>] [<a href="https://doi.org/10.1136/jmg.2009.066613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19508969">Otto et al. (2009)</a> identified compound heterozygosity for 2 mutations in the TMEM67 gene: I833T and R208X (<a href="#0011">609884.0011</a>). The patient had end-stage renal failure at age 16, liver fibrosis, mental retardation, and cerebellar vermis aplasia. Ocular involvement was not observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19508969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a German girl with Joubert syndrome, <a href="#7" class="mim-tip-reference" title="Dafinger, C., Liebau, M. C., Elsayed, S. M., Hellenbroich, Y., Boltshauser, E., Korenke, G. C., Fabretti, F., Janecke, A. R., Ebermann, I., Nurnberg, G., Nurnberg, P., Zentgraf, H., Koerber, F., Addicks, K., Elsobky, E., Benzing, T., Schermer, B., Bolz, H. J. <strong>Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics.</strong> J. Clin. Invest. 121: 2662-2667, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21633164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21633164</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21633164[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/10.1172/JCI43639" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21633164">Dafinger et al. (2011)</a> identified compound heterozygosity for 2 mutations in the TMEM67 gene: I833T and pro358 to leu (P358L; <a href="#0024">609884.0024</a>). She also had a heterozygous 12-bp deletion in the KIF7 gene (3986del12; <a href="/entry/611254#0008">611254.0008</a>). The patient had mental retardation, molar tooth sign on brain MRI, ataxia, hypertelorism, low-set ears, coloboma, and elevated liver enzymes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21633164" 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">rs786200867 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786200867;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=rs786200867" 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=rs786200867" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the splice site mutation in intron 24 of the TMEM67 gene (2556+1G-T) that was found in compound heterozygous state in patients with COACH syndrome (COACH1; <a href="/entry/216360">216360</a>) by <a href="#5" class="mim-tip-reference" title="Brancati, F., Iannicelli, M., Travaglini, L., Mazzotta, A., Bertini, E., Boltshauser, E., D'Arrigo, S., Emma, F., Fazzi, E., Gallizzi, R., Gentile, M., Loncarevic, D., and 12 others. <strong>MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement.</strong> Hum. Mutat. 30: E432-E442, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19058225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19058225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19058225[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.20924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19058225">Brancati et al. (2009)</a>, see <a href="#0013">609884.0013</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19058225" 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> rs786200868 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786200868;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/rs786200868?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=rs786200868" 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=rs786200868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the splice site mutation in intron 2 of the TMEM67 gene (312+5G-A) that was found in compound heterozygous state in patients with COACH syndrome (COACH1; <a href="/entry/216360">216360</a>) by <a href="#5" class="mim-tip-reference" title="Brancati, F., Iannicelli, M., Travaglini, L., Mazzotta, A., Bertini, E., Boltshauser, E., D'Arrigo, S., Emma, F., Fazzi, E., Gallizzi, R., Gentile, M., Loncarevic, D., and 12 others. <strong>MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement.</strong> Hum. Mutat. 30: E432-E442, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19058225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19058225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19058225[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.20924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19058225">Brancati et al. (2009)</a>, see <a href="#0013">609884.0013</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19058225" 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> rs267607115 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607115;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/rs267607115?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=rs267607115" 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=rs267607115" 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=RCV000001449 OR RCV000201677 OR RCV001781164 OR RCV001851546 OR RCV005049308" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001449, RCV000201677, RCV001781164, RCV001851546, RCV005049308" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001449...</a>
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<p>In 2 Italian brothers with COACH syndrome (COACH1; <a href="/entry/216360">216360</a>) reported by <a href="#12" class="mim-tip-reference" title="Gentile, M., Di Carlo, A., Susca, F., Gambotto, A., Caruso, M. L., Panella, C., Vajro, P., Guanti, G. <strong>COACH syndrome: report of two brothers with congenital hepatic fibrosis, cerebellar vermis hypoplasia, oligophrenia, ataxia, and mental retardation.</strong> Am. J. Med. Genet. 64: 514-520, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8862632/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8862632</a>] [<a href="https://doi.org/10.1002/(SICI)1096-8628(19960823)64:3<514::AID-AJMG13>3.0.CO;2-O" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8862632">Gentile et al. (1996)</a>, <a href="#5" class="mim-tip-reference" title="Brancati, F., Iannicelli, M., Travaglini, L., Mazzotta, A., Bertini, E., Boltshauser, E., D'Arrigo, S., Emma, F., Fazzi, E., Gallizzi, R., Gentile, M., Loncarevic, D., and 12 others. <strong>MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement.</strong> Hum. Mutat. 30: E432-E442, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19058225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19058225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19058225[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.20924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19058225">Brancati et al. (2009)</a> identified compound heterozygosity for 2 mutations in the TMEM67 gene: a 1769T-C transition in exon 17, resulting in a phe590-to-ser (F590S) substitution, and a splice site mutation in intron 19 (1961-2A-C; <a href="#0017">609884.0017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19058225+8862632" 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> rs758948621 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs758948621;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/rs758948621?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=rs758948621" 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=rs758948621" 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=RCV000001441 OR RCV000201576" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001441, RCV000201576" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001441...</a>
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<p>For discussion of the splice mutation in intron 19 of the TMEM67 gene (1961-2A-C) that was found in compound heterozygous state in patients with COACH syndrome (COACH1; <a href="/entry/216360">216360</a>) by <a href="#5" class="mim-tip-reference" title="Brancati, F., Iannicelli, M., Travaglini, L., Mazzotta, A., Bertini, E., Boltshauser, E., D'Arrigo, S., Emma, F., Fazzi, E., Gallizzi, R., Gentile, M., Loncarevic, D., and 12 others. <strong>MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement.</strong> Hum. Mutat. 30: E432-E442, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19058225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19058225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19058225[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.20924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19058225">Brancati et al. (2009)</a>, see <a href="#0016">609884.0016</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19058225" 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">rs267607116 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607116;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=rs267607116" 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=rs267607116" 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=RCV000001450 OR RCV000587331" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001450, RCV000587331" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001450...</a>
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<p>In 3 sibs, born of consanguineous Turkish parents, with nephronophthisis and hepatic fibrosis (NPHP11; <a href="/entry/613550">613550</a>), <a href="#15" class="mim-tip-reference" title="Otto, E. A., Tory, K., Attanasio, M., Zhou, W., Chaki, M., Paruchuri, Y., Wise, E. L., Wolf, M. T. F., Utsch, B., Becker, C., Nurnberg, G., Nurnberg, P., Nayir, A., Saunier, S., Antignac, C., Hildebrandt, F. <strong>Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).</strong> J. Med. Genet. 46: 663-670, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19508969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19508969</a>] [<a href="https://doi.org/10.1136/jmg.2009.066613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19508969">Otto et al. (2009)</a> identified a homozygous 2461G-A transition in exon 24 of the TMEM67 gene, resulting in a gly821-to-ser (G821S) substitution in a highly conserved residue. The mutation was not found in 188 controls or in 147 ethnically matched controls. The patients developed end-stage renal disease between ages 9 and 14 years and had no neurologic abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19508969" 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 id="0019" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0019 NEPHRONOPHTHISIS 11</strong>
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JOUBERT SYNDROME 6, INCLUDED
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TMEM67, CYS615ARG
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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> rs201893408 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs201893408;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/rs201893408?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=rs201893408" 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=rs201893408" 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=RCV000001451 OR RCV000001452 OR RCV000234823 OR RCV000283682 OR RCV000415055 OR RCV000479077 OR RCV000534533 OR RCV000623857 OR RCV000627004 OR RCV000763610 OR RCV001197497 OR RCV005041963" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001451, RCV000001452, RCV000234823, RCV000283682, RCV000415055, RCV000479077, RCV000534533, RCV000623857, RCV000627004, RCV000763610, RCV001197497, RCV005041963" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001451...</a>
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<p><strong><em>Nephronophthisis 11</em></strong></p><p>
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In a Turkish patient, born of consanguineous parents, with nephronophthisis-11 and hepatic fibrosis (NPHP11; <a href="/entry/613550">613550</a>), <a href="#15" class="mim-tip-reference" title="Otto, E. A., Tory, K., Attanasio, M., Zhou, W., Chaki, M., Paruchuri, Y., Wise, E. L., Wolf, M. T. F., Utsch, B., Becker, C., Nurnberg, G., Nurnberg, P., Nayir, A., Saunier, S., Antignac, C., Hildebrandt, F. <strong>Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).</strong> J. Med. Genet. 46: 663-670, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19508969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19508969</a>] [<a href="https://doi.org/10.1136/jmg.2009.066613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19508969">Otto et al. (2009)</a> identified a homozygous 1843T-C transition in exon 18 of the TMEM67 gene, resulting in a cys615-to-arg (C615R) substitution in a highly conserved residue. A German patient was also found to be homozygous for the mutation, and haplotype analysis indicated a common founder. The Turkish patient had end-stage renal failure at age 6, liver fibrosis, retinal degeneration, and mild cortical atrophy. The German patient had end-stage renal failure at age 6, liver fibrosis, Ehlers-Danlos syndrome, and no ocular or neurologic involvement. Another German patient with NPHP, liver fibrosis, strabismus, nystagmus, and mild 'statomotoric' retardation was found to be compound heterozygous for C615R and an 869G-T transversion in exon 8, resulting in a trp290-to-leu (W290L; <a href="#0020">609884.0020</a>) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19508969" 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>Joubert Syndrome 6</em></strong></p><p>
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<a href="#15" class="mim-tip-reference" title="Otto, E. A., Tory, K., Attanasio, M., Zhou, W., Chaki, M., Paruchuri, Y., Wise, E. L., Wolf, M. T. F., Utsch, B., Becker, C., Nurnberg, G., Nurnberg, P., Nayir, A., Saunier, S., Antignac, C., Hildebrandt, F. <strong>Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).</strong> J. Med. Genet. 46: 663-670, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19508969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19508969</a>] [<a href="https://doi.org/10.1136/jmg.2009.066613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19508969">Otto et al. (2009)</a> reported a patient with Joubert syndrome-6 (JBTS6; <a href="/entry/610688">610688</a>) who was compound heterozygous for C615R and a 755T-C transition in exon 8 of the TMEM67 gene, resulting in a met252-to-thr (M252T; <a href="#0023">609884.0023</a>) substitution. The patient had end-stage renal failure at age 14, hepatic fibrosis, nystagmus, oculomotor apraxia, chorioretinal coloboma, ataxia, and psychomotor retardation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19508969" 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>.0020 NEPHRONOPHTHISIS 11</strong>
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TMEM67, TRP290LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267607117 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607117;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=rs267607117" 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=rs267607117" 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=RCV000001453" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001453" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001453</a>
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<p>For discussion of the trp290-to-leu (W290L) mutation in the TMEM67 gene that was found in compound heterozygous state in a patient with nephronophthisis-11 (NPHP11; <a href="/entry/613550">613550</a>) by <a href="#15" class="mim-tip-reference" title="Otto, E. A., Tory, K., Attanasio, M., Zhou, W., Chaki, M., Paruchuri, Y., Wise, E. L., Wolf, M. T. F., Utsch, B., Becker, C., Nurnberg, G., Nurnberg, P., Nayir, A., Saunier, S., Antignac, C., Hildebrandt, F. <strong>Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).</strong> J. Med. Genet. 46: 663-670, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19508969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19508969</a>] [<a href="https://doi.org/10.1136/jmg.2009.066613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19508969">Otto et al. (2009)</a>, see <a href="#0019">609884.0019</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19508969" 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>.0021 NEPHRONOPHTHISIS 11</strong>
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JOUBERT SYNDROME 6, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267607116 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607116;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=rs267607116" 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=rs267607116" 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=RCV000001454 OR RCV000001455" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001454, RCV000001455" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001454...</a>
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<p>In a German patient with nephronophthisis-11 and hepatic fibrosis (NPHP11; <a href="/entry/613550">613550</a>), <a href="#15" class="mim-tip-reference" title="Otto, E. A., Tory, K., Attanasio, M., Zhou, W., Chaki, M., Paruchuri, Y., Wise, E. L., Wolf, M. T. F., Utsch, B., Becker, C., Nurnberg, G., Nurnberg, P., Nayir, A., Saunier, S., Antignac, C., Hildebrandt, F. <strong>Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).</strong> J. Med. Genet. 46: 663-670, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19508969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19508969</a>] [<a href="https://doi.org/10.1136/jmg.2009.066613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19508969">Otto et al. (2009)</a> identified a homozygous 2461G-C transversion in exon 24 of the TMEM67 gene, resulting in a gly821-to-arg (G821R) substitution. The patient developed end-stage renal failure at age 10 years, and also had anisocoria and psychomotor retardation, but normal brain MRI findings. An unrelated German patient with a more severe phenotype, consistent with Joubert syndrome-6 (JBTS6; <a href="/entry/610688">610688</a>), was compound heterozygous for G821R and a 130C-T transition in exon 1, resulting in a gln44-to-ter (Q44X; <a href="#0022">609884.0022</a>) substitution. The patient with Joubert syndrome had end-stage renal failure at age 12, retinal degeneration, chorioretinal coloboma, ataxia, and cerebellar vermis aplasia. Liver involvement was not reported. Haplotype analysis of both patients indicated a common origin for the G821R mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19508969" 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> rs267607118 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607118;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/rs267607118?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=rs267607118" 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=rs267607118" 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=RCV000001456 OR RCV001851547" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001456, RCV001851547" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001456...</a>
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<p>For discussion of the gln44-to-ter (Q44X) mutation in the TMEM67 gene that was found in compound heterozygous state in a patient with Joubert syndrome-6 (JBTS6; <a href="/entry/610688">610688</a>) by <a href="#15" class="mim-tip-reference" title="Otto, E. A., Tory, K., Attanasio, M., Zhou, W., Chaki, M., Paruchuri, Y., Wise, E. L., Wolf, M. T. F., Utsch, B., Becker, C., Nurnberg, G., Nurnberg, P., Nayir, A., Saunier, S., Antignac, C., Hildebrandt, F. <strong>Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).</strong> J. Med. Genet. 46: 663-670, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19508969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19508969</a>] [<a href="https://doi.org/10.1136/jmg.2009.066613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19508969">Otto et al. (2009)</a>, see <a href="#0021">609884.0021</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19508969" 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> rs202149403 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs202149403;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/rs202149403?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=rs202149403" 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=rs202149403" 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=RCV000001457 OR RCV000234813 OR RCV000418247 OR RCV001389251 OR RCV002490292 OR RCV004689399 OR RCV004732521" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001457, RCV000234813, RCV000418247, RCV001389251, RCV002490292, RCV004689399, RCV004732521" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001457...</a>
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<p>For discussion of the met252-to-thr (M252T) mutation in the TMEM67 gene that was found in compound heterozygous state in a patient with Joubert syndrome-6 (JBTS6; <a href="/entry/610688">610688</a>) by <a href="#15" class="mim-tip-reference" title="Otto, E. A., Tory, K., Attanasio, M., Zhou, W., Chaki, M., Paruchuri, Y., Wise, E. L., Wolf, M. T. F., Utsch, B., Becker, C., Nurnberg, G., Nurnberg, P., Nayir, A., Saunier, S., Antignac, C., Hildebrandt, F. <strong>Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).</strong> J. Med. Genet. 46: 663-670, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19508969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19508969</a>] [<a href="https://doi.org/10.1136/jmg.2009.066613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19508969">Otto et al. (2009)</a>, see <a href="#0019">609884.0019</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19508969" 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">rs863225232 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225232;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=rs863225232" 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=rs863225232" 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=RCV000201590 OR RCV004528990" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000201590, RCV004528990" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000201590...</a>
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<p>For discussion of the pro358-to-leu (P358L) mutation in the TMEM67 gene that was found in compound heterozygous state in a patient with Joubert syndrome-6 (JBTS6; <a href="/entry/610688">610688</a>) by <a href="#7" class="mim-tip-reference" title="Dafinger, C., Liebau, M. C., Elsayed, S. M., Hellenbroich, Y., Boltshauser, E., Korenke, G. C., Fabretti, F., Janecke, A. R., Ebermann, I., Nurnberg, G., Nurnberg, P., Zentgraf, H., Koerber, F., Addicks, K., Elsobky, E., Benzing, T., Schermer, B., Bolz, H. J. <strong>Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics.</strong> J. Clin. Invest. 121: 2662-2667, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21633164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21633164</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21633164[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/10.1172/JCI43639" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21633164">Dafinger et al. (2011)</a>, see <a href="#0013">609884.0013</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21633164" 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">rs786205126 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205126;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=rs786205126" 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=rs786205126" 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=RCV000049341" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049341" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049341</a>
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<p>In a patient from a consanguineous family who presented with Meckel syndrome type 3 (MKS3; <a href="/entry/607361">607361</a>) and cerebellar heterotopia, <a href="#2" class="mim-tip-reference" title="Adams, M., Simms, R. J., Abdelhamed, Z., Dawe, H. R., Szymanska, K., Logan, C. V., Wheway, G., Pitt, E., Gull, K., Knowles, M. A., Blair, E., Cross, S. H., Sayer, J. A., Johnson, C. A. <strong>A meckelin-filamin A interaction mediates ciliogenesis.</strong> Hum. Molec. Genet. 21: 1272-1286, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22121117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22121117</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22121117[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddr557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22121117">Adams et al. (2012)</a> identified a homozygous 3-bp deletion, c.2754_2756delCTT, resulting in an in-frame deletion of phe919 (919delF) in the C-terminal cytoplasmic region of meckelin. The deletion abrogated the interaction of meckelin with filamin A (FLNA; <a href="/entry/300017">300017</a>), resulting in aberrant hyperactivation of canonical Wnt signaling in patient fibroblasts compared with controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22121117" 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">rs967792092 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs967792092;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=rs967792092" 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=rs967792092" 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=RCV000723363" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000723363" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000723363</a>
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<p>For discussion of the c.1289A-G transition (c.1289A-G, NM_153704.5) in exon 13 of the TMEM67 gene, resulting in an asp430-to-gly (D430G) substitution, that was found in compound heterozygous state in a 38-year-old Italian man with RHYNS syndrome (<a href="/entry/602152">602152</a>) by <a href="#4" class="mim-tip-reference" title="Brancati, F., Camerota, L., Colao, E., Vega-Warner, V., Zhao, X., Zhang, R., Bottillo, I., Castori, M., Caglioti, A., Sangiuolo, F., Novelli, G., Perrotti, N., and 16 others. <strong>Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome.</strong> Europ. J. Hum. Genet. 26: 1266-1271, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29891882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29891882</a>] [<a href="https://doi.org/10.1038/s41431-018-0183-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29891882">Brancati et al. (2018)</a>, see <a href="#0011">609884.0011</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29891882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 20-year-old Korean man with COACH syndrome-1 (COACH1; <a href="/entry/216360">216360</a>), <a href="#13" class="mim-tip-reference" title="Lee, S.-H., Nam, T.-S., Li, W., Kim, J. H., Yoon, W., Choi, Y.-D., Kim, K.-H., Cai, H., Kim, M. J., Kim, C., Choy H. E., Kim, N., Chay, K. O., Kim, M.-K,, Choi, S.-Y. <strong>Functional validation of novel MKS3/TMEM67 mutations in COACH syndrome.</strong> Sci. Rep. 7: 10222, 2017. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28860541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28860541</a>] [<a href="https://doi.org/10.1038/s41598-017-10652-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28860541">Lee et al. (2017)</a> identified compound heterozygous mutations in the TMEM67 gene: a c.395G-C transversion (c.395G-C, NM_153704.5) in exon 3, resulting in a gly132-to-ala (G132A) substitution in the cysteine-rich region, and a 1-bp deletion (c.2758delT; 609884.0028) in exon 26, resulting in a frameshift and premature termination (Tyr920ThrfsTer40). Both mutations occurred at highly conserved residues. The mutations were found by sequencing of the TMEM67 gene. The father was heterozygous for the mutation, but the mother was not tested. Transfection experiments in HEK293T cells showed that the c.2758delT mutation resulted in decreased stability and increased turnover of the protein, and the G132A mutation resulted in decreased mRNA expression, compared to wildtype. In TMEM67 <a href="#13" class="mim-tip-reference" title="Lee, S.-H., Nam, T.-S., Li, W., Kim, J. H., Yoon, W., Choi, Y.-D., Kim, K.-H., Cai, H., Kim, M. J., Kim, C., Choy H. E., Kim, N., Chay, K. O., Kim, M.-K,, Choi, S.-Y. <strong>Functional validation of novel MKS3/TMEM67 mutations in COACH syndrome.</strong> Sci. Rep. 7: 10222, 2017. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28860541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28860541</a>] [<a href="https://doi.org/10.1038/s41598-017-10652-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28860541">Lee et al. (2017)</a> also showed that in TMEM67 knockdown zebrafish with a hydrocephalus phenotype, injection with mutant morpholinos containing the G132A or c.2758delT mutations did not rescue the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28860541" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>For discussion of the 1-bp deletion (c.2758delT, NM_153704.5) in the TMEM67 gene that was found in compound heterozygous state in a patient with COACH syndrome-1 (COACH1; <a href="/entry/216360">216360</a>) by <a href="#13" class="mim-tip-reference" title="Lee, S.-H., Nam, T.-S., Li, W., Kim, J. H., Yoon, W., Choi, Y.-D., Kim, K.-H., Cai, H., Kim, M. J., Kim, C., Choy H. E., Kim, N., Chay, K. O., Kim, M.-K,, Choi, S.-Y. <strong>Functional validation of novel MKS3/TMEM67 mutations in COACH syndrome.</strong> Sci. Rep. 7: 10222, 2017. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28860541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28860541</a>] [<a href="https://doi.org/10.1038/s41598-017-10652-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28860541">Lee et al. (2017)</a>, see <a href="#0027">609884.0027</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28860541" 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>REFERENCES</strong>
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<a id="Abdelhamed2013" class="mim-anchor"></a>
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Abdelhamed, Z. A., Wheway, G., Szymanska, K., Natarajan, S., Toomes, C., Inglehearn, C., Johnson, C. A.
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<strong>Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects.</strong>
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Hum. Molec. Genet. 22: 1358-1372, 2013.
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[<a href="https://doi.org/10.1093/hmg/dds546" target="_blank">Full Text</a>]
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Adams, M., Simms, R. J., Abdelhamed, Z., Dawe, H. R., Szymanska, K., Logan, C. V., Wheway, G., Pitt, E., Gull, K., Knowles, M. A., Blair, E., Cross, S. H., Sayer, J. A., Johnson, C. A.
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<strong>A meckelin-filamin A interaction mediates ciliogenesis.</strong>
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Hum. Molec. Genet. 21: 1272-1286, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22121117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22121117</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22121117[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=22121117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddr557" target="_blank">Full Text</a>]
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Baala, L., Romano, S., Khaddour, R., Saunier, S., Smith, U. M., Audollent, S., Ozilou, C., Faivre, L., Laurent, N., Foliguet, B., Munnich, A., Lyonnet, S., and 9 others.
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<strong>The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome.</strong>
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Am. J. Hum. Genet. 80: 186-194, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17160906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17160906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17160906[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=17160906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/510499" target="_blank">Full Text</a>]
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Brancati, F., Camerota, L., Colao, E., Vega-Warner, V., Zhao, X., Zhang, R., Bottillo, I., Castori, M., Caglioti, A., Sangiuolo, F., Novelli, G., Perrotti, N., and 16 others.
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<strong>Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome.</strong>
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Europ. J. Hum. Genet. 26: 1266-1271, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29891882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29891882</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29891882" 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/s41431-018-0183-6" target="_blank">Full Text</a>]
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Brancati, F., Iannicelli, M., Travaglini, L., Mazzotta, A., Bertini, E., Boltshauser, E., D'Arrigo, S., Emma, F., Fazzi, E., Gallizzi, R., Gentile, M., Loncarevic, D., and 12 others.
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<strong>MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement.</strong>
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Hum. Mutat. 30: E432-E442, 2009. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19058225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19058225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19058225[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=19058225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.20924" target="_blank">Full Text</a>]
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Consugar, M. B., Kubly, V. J., Lager, D. J., Hommerding, C. J., Wong, W. C., Bakker, E., Gattone, V. H., II, Torres, V. E., Breuning, M. H., Harris, P. C.
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<strong>Molecular diagnostics of Meckel-Gruber syndrome highlights phenotypic differences between MKS1 and MKS3.</strong>
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Hum. Genet. 121: 591-599, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17377820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17377820</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17377820" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-007-0341-3" target="_blank">Full Text</a>]
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<a id="Dafinger2011" class="mim-anchor"></a>
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Dafinger, C., Liebau, M. C., Elsayed, S. M., Hellenbroich, Y., Boltshauser, E., Korenke, G. C., Fabretti, F., Janecke, A. R., Ebermann, I., Nurnberg, G., Nurnberg, P., Zentgraf, H., Koerber, F., Addicks, K., Elsobky, E., Benzing, T., Schermer, B., Bolz, H. J.
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<strong>Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics.</strong>
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J. Clin. Invest. 121: 2662-2667, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21633164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21633164</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21633164[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=21633164" 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/10.1172/JCI43639" target="_blank">Full Text</a>]
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Dawe, H. R., Smith, U. M., Cullinane, A. R., Gerrelli, D., Cox, P., Badano, J. L., Blair-Reid, S., Sriram, N., Katsanis, N., Attie-Bitach, T., Afford, S. C., Copp, A. J., Kelly, D. A., Gull, K., Johnson, C. A.
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<strong>The Meckel-Gruber syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation.</strong>
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Hum. Molec. Genet. 16: 173-186, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17185389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17185389</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17185389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddl459" target="_blank">Full Text</a>]
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Di Rocco, M., Picco, P., Arslanian, A., Restagno, G., Perfumo, F., Buoncompagni, A., Gattorno, M., Borrone, C.
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<strong>Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): a new syndrome?</strong>
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Am. J. Med. Genet. 73: 1-4, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9375913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9375913</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9375913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/(sici)1096-8628(19971128)73:1<1::aid-ajmg1>3.0.co;2-y" target="_blank">Full Text</a>]
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<a id="Doherty2010" class="mim-anchor"></a>
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Doherty, D., Parisi, M. A., Finn, L. S., Gunay-Aygun, M., Al-Mateen, M., Bates, D., Clericuzio, C., Demir, H., Dorschner, M., van Essen, A. J., Gahl, W. A., Gentile, M., and 11 others.
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<strong>Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis).</strong>
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J. Med. Genet. 47: 8-21, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19574260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19574260</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19574260[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=19574260" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2009.067249" target="_blank">Full Text</a>]
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<a id="Garcia-Gonzalo2011" class="mim-anchor"></a>
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Garcia-Gonzalo, F. R., Corbit, K. C., Sirerol-Piquer, M. S., Ramaswami, G., Otto, E. A., Noriega, T. R., Seol, A. D., Robinson, J. F., Bennett, C. L., Josifova, D. J., Garcia-Verdugo, J. M., Katsanis, N., Hildebrandt, F., Reiter, J. F.
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<strong>A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition.</strong>
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Nature Genet. 43: 776-784, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21725307/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21725307</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21725307[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=21725307" 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.891" target="_blank">Full Text</a>]
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<strong>COACH syndrome: report of two brothers with congenital hepatic fibrosis, cerebellar vermis hypoplasia, oligophrenia, ataxia, and mental retardation.</strong>
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Am. J. Med. Genet. 64: 514-520, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8862632/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8862632</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8862632" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/(SICI)1096-8628(19960823)64:3<514::AID-AJMG13>3.0.CO;2-O" target="_blank">Full Text</a>]
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<a id="Lee2017" class="mim-anchor"></a>
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Lee, S.-H., Nam, T.-S., Li, W., Kim, J. H., Yoon, W., Choi, Y.-D., Kim, K.-H., Cai, H., Kim, M. J., Kim, C., Choy H. E., Kim, N., Chay, K. O., Kim, M.-K,, Choi, S.-Y.
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<strong>Functional validation of novel MKS3/TMEM67 mutations in COACH syndrome.</strong>
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Sci. Rep. 7: 10222, 2017. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28860541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28860541</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28860541" 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/s41598-017-10652-z" target="_blank">Full Text</a>]
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<a id="Leitch2008" class="mim-anchor"></a>
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Leitch, C. C., Zaghloul, N. A., Davis, E. E., Stoetzel, C., Diaz-Font, A., Rix, S., Al-Fadhel, M., Lewis, R. A., Eyaid, W., Banin, E., Dollfus, H., Beales, P. L., Badano, J. L., Katsanis, N.
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<strong>Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome.</strong>
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Nature Genet. 40: 443-448, 2008. Note: Erratum: Nature Genet. 40: 927 only, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18327255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18327255</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18327255" 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.97" target="_blank">Full Text</a>]
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Otto, E. A., Tory, K., Attanasio, M., Zhou, W., Chaki, M., Paruchuri, Y., Wise, E. L., Wolf, M. T. F., Utsch, B., Becker, C., Nurnberg, G., Nurnberg, P., Nayir, A., Saunier, S., Antignac, C., Hildebrandt, F.
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<strong>Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).</strong>
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J. Med. Genet. 46: 663-670, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19508969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19508969</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19508969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2009.066613" target="_blank">Full Text</a>]
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Romano, S., Boddaert, N., Desguerre, I., Hubert, L., Salomon, R., Seidenwurm, D., Bahi-Buisson, N., Nabbout, R., Sonigo, P., Lyonnet, S., Brunelle, F., Munnich, A., de Lonlay, P.
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<strong>Molar tooth sign and superior vermian dysplasia: a radiological, clinical, and genetic study.</strong>
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Neuropediatrics 37: 42-45, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16541367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16541367</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16541367" 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/10.1055/s-2006-923838" target="_blank">Full Text</a>]
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Smith, U. R., Consugar, M., Tee, L. J., McKee, B. M., Maina, E. N., Whelan, S., Morgan, N. V., Goranson, E., Gissen, P., Lilliquist, S., Aligianis, I. A., Ward, C. J., and 19 others.
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<strong>The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and wpk rat.</strong>
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Nature Genet. 38: 191-196, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16415887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16415887</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16415887" 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/ng1713" target="_blank">Full Text</a>]
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Tammachote, R., Hommerding, C. J., Sinders, R. M., Miller, C. A., Czarnecki, P. G., Leightner, A. C., Salisbury, J. L., Ward, C. J., Torres, V. E., Gattone, V. H., II, Harris, P. C.
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<strong>Ciliary and centrosomal defects associated with mutation and depletion of the Meckel syndrome genes MKS1 and MKS3.</strong>
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Hum. Molec. Genet. 18: 3311-3323, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19515853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19515853</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19515853[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=19515853" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp272" target="_blank">Full Text</a>]
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Verloes, A., Lambotte, C.
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<strong>Further delineation of a syndrome of cerebellar vermis hypo/aplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis.</strong>
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Am. J. Med. Genet. 32: 227-232, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2929661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2929661</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2929661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320320217" target="_blank">Full Text</a>]
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Williams, C. L., Li, C., Kida, K., Inglis, P. N., Mohan, S., Semenec, L., Bialas, N. J., Stupay, R. M., Chen, N., Blacque, O. E., Yoder, B. K., Leroux, M. R.
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<strong>MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis.</strong>
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J. Cell. Biol. 192: 1023-1041, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21422230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21422230</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21422230[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=21422230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1083/jcb.201012116" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 03/11/2021
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Marla J. F. O'Neill - updated : 12/03/2018<br>Cassandra L. Kniffin - updated : 8/8/2013<br>Patricia A. Hartz - updated : 7/19/2013<br>Patricia A. Hartz - updated : 7/16/2013<br>Cassandra L. Kniffin - updated : 8/18/2011<br>Cassandra L. Kniffin - updated : 8/18/2011<br>Patricia A. Hartz - updated : 4/29/2011<br>Cassandra L. Kniffin - updated : 9/3/2010<br>George E. Tiller - updated : 7/7/2010<br>Patricia A. Hartz - updated : 6/25/2010<br>Ada Hamosh - updated : 5/7/2008<br>Cassandra L. Kniffin - updated : 6/6/2007<br>Victor A. McKusick - updated : 1/3/2007
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Victor A. McKusick : 2/9/2006
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carol : 12/01/2020<br>carol : 12/04/2018<br>alopez : 12/03/2018<br>carol : 08/09/2016<br>carol : 03/23/2015<br>mcolton : 3/20/2015<br>alopez : 10/17/2014<br>carol : 10/9/2013<br>carol : 8/14/2013<br>ckniffin : 8/8/2013<br>joanna : 8/5/2013<br>carol : 7/19/2013<br>mgross : 7/16/2013<br>carol : 2/7/2012<br>alopez : 8/23/2011<br>ckniffin : 8/18/2011<br>ckniffin : 8/18/2011<br>joanna : 6/6/2011<br>mgross : 5/19/2011<br>mgross : 5/19/2011<br>terry : 4/29/2011<br>carol : 9/7/2010<br>ckniffin : 9/3/2010<br>wwang : 7/21/2010<br>terry : 7/7/2010<br>mgross : 6/30/2010<br>terry : 6/25/2010<br>wwang : 6/24/2010<br>ckniffin : 6/16/2010<br>joanna : 4/1/2009<br>alopez : 7/14/2008<br>alopez : 5/23/2008<br>terry : 5/7/2008<br>wwang : 6/14/2007<br>ckniffin : 6/6/2007<br>alopez : 1/8/2007<br>terry : 1/3/2007<br>alopez : 2/9/2006
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<h3>
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<span class="mim-font">
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<strong>*</strong> 609884
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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TRANSMEMBRANE PROTEIN 67; TMEM67
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</span>
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</h3>
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</div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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MKS3 GENE<br />
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MECKELIN
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</span>
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</h4>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TMEM67</em></strong>
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</span>
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</p>
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</div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 723999009;
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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: 8q22.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 8:93,754,844-93,832,653 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</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="6">
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<span class="mim-font">
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8q22.1
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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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?RHYNS syndrome
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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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602152
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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<tr>
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<td>
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<span class="mim-font">
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{Bardet-Biedl syndrome 14, modifier of}
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</td>
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<td>
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<span class="mim-font">
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615991
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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COACH syndrome 1
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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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216360
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Joubert syndrome 6
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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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610688
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Meckel syndrome 3
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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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607361
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Nephronophthisis 11
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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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613550
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Smith et al. (2006) refined mapping of a Meckel syndrome locus (MKS3; 607361) to a 12.67-Mb interval on chromosome 8q21.13-q22.1, which is syntenic to the Wpk locus in rat. Positional cloning of the Wpk gene suggested an MKS3 candidate gene, TMEM67 (transmembrane protein-67). The human TMEM67 gene encodes a deduced 995-amino acid protein, which the authors called meckelin, with a calculated unglycosylated mass of 108 kD. Human and rat meckelin share 84% identity. Meckelin was predicted to contain a signal peptide, at least 2 cysteine-rich repeats, and a 490-residue extracellular region with 4 N-linked glycosylated sites, followed by 7 transmembrane domains and a 30-residue cytoplasmic tail. RNA blotting identified a primary transcript of 4.0 kb and a weaker product of 4.5 kb expressed in all adult and fetal human tissues tested. Real-time quantitative PCR analysis of human embryonic tissues detected highest expression in spinal cord and moderate levels in adrenal tissue, brain, and kidney. </p><p>Using in situ hybridization with human embryos, Dawe et al. (2007) found that meckelin was expressed in kidney, liver, retina, hindbrain, developing sphenoid bone, and the brain midline. Intense expression was also detected in cartilage of developing limbs, particularly in the digits. Immunohistochemical analysis of 18- to 20-week-old human fetal kidneys detected moderate to high expression of meckelin and MKS1 (609883) at the proximal renal tubule epithelia, but not at glomeruli. In liver, these proteins were also expressed at the biliary epithelium of larger bile ducts, but not in hepatocytes. In HEK293 cells, meckelin was expressed at the cell border and colocalized with alpha-tubulin (see 602529) at primary cilia. Western blot analysis detected meckelin at an apparent molecular mass of 120 kD. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By sequence analysis, Smith et al. (2006) mapped the TMEM67 gene to chromosome 8q21.13-q22.1. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using RNA interference, Dawe et al. (2007) found that knockdown of either Mks1 or Mks3 in mouse inner medullary IMCD-3 cells blocked centriole migration to the apical membrane and formation of the primary cilium. Coimmunoprecipitation experiments showed that wildtype Mks1 and Mks3 interacted, and knockdown of either Mks1 or Mks3 in IMCD-3 cells decreased the formation of highly branched structures and tubules in 3-dimensional cultures. Dawe et al. (2007) concluded that MKS1 and MKS3 have roles in ciliogenesis and renal tubulogenesis. </p><p>Tammachote et al. (2009) showed that kidney tissue and cells from MKS1 (249000) and MKS3 patients showed defects in centrosome and cilia number, including multiciliated respiratory-like epithelia, and longer cilia. Stable shRNA knockdown of Mks1 and Mks3 in IMCD-3 cells induced multiciliated and multicentrosomal phenotypes. MKS1 and MKS3 functions are required for ciliary structure and function, including a role in regulating length and appropriate number through modulating centrosome duplication. Tammachote et al. (2009) concluded that MKS1 and MKS3 are ciliopathies, with new cilia-related eye and sperm phenotypes defined. </p><p>Williams et al. (2011) showed that the conserved proteins Mks1, Mksr1 (B9D1; 614144), Mksr2 (B9D2; 611951), Tmem67, Rpgrip1l (610937), Cc2d2a (612013), Nphp1 (607100), and Nphp4 (607215) functioned at an early stage of ciliogenesis in C. elegans. These 8 proteins localized to the ciliary transition zone and established attachments between the basal body and transition zone membrane. They also provided a docking site that restricted vesicle fusion to vesicles containing ciliary proteins. </p><p>By yeast 2-hybrid and immunoprecipitation analyses, Adams et al. (2012) found that the C-terminal cytoplasmic tail of meckelin interacted with filamin A (FLNA; 300017). Loss of filamin A or meckelin in immortalized fibroblasts from patients with null mutations in the genes or by small interfering RNA in mouse IMCD3 cells resulted in similar cellular phenotypes, including abnormal basal body positioning and ciliogenesis, aberrant remodeling of the actin cytoskeleton, deregulation of RHOA (165390) activity, and hyperactivation of canonical Wnt (see 606359) signaling. Adams et al. (2012) concluded that the meckelin-filamin A signaling axis is a key regulator of ciliogenesis and normal Wnt signaling. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Meckel Syndrome 3</em></strong></p><p>
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In 5 consanguineous families with Meckel syndrome linked to chromosome 8q21.13-q22.1 (MKS3; 607361), Smith et al. (2006) detected 5 different homozygous mutations in the TMEM67 gene (609884.0001-609884.0005). The mutations consisted of 2 frameshift deletions, 2 splicing mutations, and a nonconservative missense change. The mutations were not found in over 120 ethnically matched normal control chromosomes. </p><p>Consugar et al. (2007) identified 7 novel pathogenic mutations in the TMEM67 gene (see, e.g., 609884.0011) in 5 of 17 families with a clinical diagnosis of Meckel syndrome. </p><p><strong><em>Joubert Syndrome 6</em></strong></p><p>
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Joubert syndrome (JBTS; see 213300) is an autosomal recessive disorder characterized by cerebellar vermis hypoplasia associated with hypotonia, developmental delay, abnormal respiratory patterns, and abnormal eye movements. The association of retinal dystrophy and renal anomalies defines a subtype of JBTS. Occipital encephalocele and polydactyly have occasionally been reported in patients with JBTS. These features are also found in Meckel-Gruber syndrome. The phenotypic overlap between JBTS and Meckel-Gruber syndrome is supported by the central nervous system malformations seen in the Wpk rat model of Meckel-Gruber syndrome, which includes agenesis of the corpus callosum and hydrocephalus but not exencephaly. The missense mutation, P394L, seen in the rat Mks3 gene is presumably a hypomorphic allele because of the mild phenotype and viability of the Wpk rat (Smith et al., 2006). While sequencing MKS1 (609883) and MKS3 genes in 31 unrelated fetuses presenting a cerebrorenodigital syndrome, which was designated 'Meckel-like' because of the absence of at least 1 of the MKS diagnostic criteria, Baala et al. (2007) identified MKS3 mutations in a family with 2 sibs. The pregnancies were terminated at 30 weeks' and 28 weeks' gestation, respectively, because of abnormal posterior fossae and hyperechogenic, enlarged kidneys detected by ultrasound. Kidney pathology in both fetuses showed liver bile duct proliferation and microcysts mainly in the medulla. Abnormalities in the brainstem resembling those of Joubert syndrome were described. The 2 sibs were found to be compound heterozygous for 2 mutations in the MKS3 gene: a missense mutation, Y513C, inherited from the father (609884.0006) and an insertion/deletion mutation inherited from the mother (609884.0007). Despite the absence of neurologic symptoms required for postnatal diagnosis in these sibs, Baala et al. (2007) questioned what MKS gene mutations could be found in patients with typical JBTS and sequenced 22 patients who had no deletion of the NPHP1 gene (607100). Sequence analysis revealed mutations in 3 patients. Studies identified the MKS3 gene as mutant in a sixth form of Joubert syndrome (JBTS6; 610688). </p><p>Otto et al. (2009) identified TMEM67 mutations (see, e.g., 609884.0011; 609884.0013; 609884.0019; 609884.0021-609884.0023) in 4 (3.3%) of 120 unrelated probands with Joubert syndrome. In 1 family another member was also affected. All 5 patients had ataxia, hypotonia or psychomotor retardation or showed cerebellar vermis hypo- or aplasia. All developed end-stage renal disease between 8 and 15 years of age, and 4 had hepatic fibrosis. Four also had ocular involvement, including blindness, retinal degeneration, or retinal coloboma. </p><p><strong><em>Bardet-Biedl Syndrome</em></strong></p><p>
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The identification of mutations in the MKS1 gene (609883) in patients with clinical diagnoses of Bardet-Biedl syndrome (BBS; 209900) led Leitch et al. (2008) to investigate other Meckel syndrome genes as contributors to the BBS phenotype. While they did not find families with 2 pathogenic alleles in the MKS3 gene, they did find 2 families harboring potentially pathogenic heterozygous alleles. In one of these families a splice-site mutation in MKS3 was found with homozygosity for a BBS9 mutation (607968). An individual from the second family carried a complex allele encoding a protein with 2 in cis changes. One of the changes was predicted to be benign; the second, S320C (609884.0012), was predicted to be pathogenic. This patient also carried a homozygous truncating mutation in CEP290 (610142.0013). </p><p><strong><em>COACH Syndrome 1</em></strong></p><p>
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COACH syndrome-1 (COACH1; 216360) is an autosomal recessive disorder originally described as including cerebellar vermis hypoplasia, oligophrenia, ataxia, ocular coloboma, and congenital hepatic fibrosis (Verloes and Lambotte, 1989). The clinical features overlap with those observed in Joubert and Meckel syndromes. In 8 (57%) of 14 families diagnosed with COACH syndrome, defined as Joubert syndrome with congenital liver fibrosis, Brancati et al. (2009) identified compound heterozygous mutations in the TMEM67 gene (see, e.g., 609884.0013-609885.0016). One of the families included the original family reported by Verloes and Lambotte (1989) (609884.0013 and 609884.0014). The phenotype in all patients was consistent with Joubert syndrome with congenital hepatic fibrosis, indicating that COACH syndrome can be considered a subtype of Joubert syndrome. The clinical variability of the disorder, relating to the extent and severity of liver and neurologic dysfunction as well as to the presence or absence of ocular and renal findings, was hypothesized to be due to genetic modifiers, similar to other ciliopathies, including Bardet-Biedl syndrome (BBS; 209900). </p><p>Doherty et al. (2010) identified mutations in the TMEM67 gene in 19 (83%) of 23 families with COACH syndrome, defined as Joubert syndrome with liver disease. In contrast, TMEM67 mutations were only found in 2 (1%) of 209 families with Joubert syndrome without liver involvement. The findings further supported the concept that COACH syndrome is a form of Joubert syndrome with hepatic fibrosis. The proposed ciliary function for TMEM67 supported a unifying underlying pathophysiology for liver disease in these disorders. </p><p>In a 20-year-old Korean man with COACH syndrome, Lee et al. (2017) identified compound heterozygous mutations in the TMEM67 gene (G132A, 609884.0027 and c.2758delT, 609884.0028). Transfection experiments in HEK293T cells showed that the c.2758delT mutation resulted in decreased stability and increased turnover of the protein, and the G132A mutation resulted in decreased mRNA expression, compared to wildtype. In TMEM67 knockdown zebrafish with a hydrocephalus phenotype, injection with mutant morpholinos containing the G132A or c.2758delT mutation did not rescue the phenotype. Injection with the 2 mutant morpholinos in the TMEM67 knockdown zebrafish also did not rescue wnt signaling defects, as evidenced by suppressed axin2 (604025) mRNA. </p><p><strong><em>Nephronophthisis 11</em></strong></p><p>
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In patients with nephronophthisis and hepatic fibrosis (NPHP11; 613550), Otto et al. (2009) identified homozygous or compound heterozygous missense mutations in the TMEM67 gene (see, e.g., 609884.0018-609884.0021). Mutations in the TMEM67 gene were not found in 105 NPHP patients without liver fibrosis, suggesting that liver fibrosis is a specific feature of TMEM67 mutations. Otto et al. (2009) concluded that mutations in TMEM67 can cause NPHP in patients with additional liver fibrosis but without neurologic involvement and with normal brain imaging, and that NPHP11, MKS3, and JBTS6 represent a spectrum of allelic disorders. </p><p><strong><em>RHYNS Syndrome</em></strong></p><p>
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In a 38-year-old Italian man with RHYNS syndrome (RHYNS; 602152), Brancati et al. (2018) identified compound heterozygosity for a nonsense mutation (R208X; 609884.0011) and a missense mutation (D430G; 609884.0026) in the TMEM67 gene. The mutations segregated with disease in the family. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Otto et al. (2009) found homozygosity or compound heterozygosity for missense mutations in the TMEM67 gene (609884.0018-609884.0021) in patients with NPHP11 and hepatic fibrosis. All patients with NPHP and hepatic fibrosis and no brain anomaly carried a missense mutation affecting either amino acid C615 or G821. Thus, Otto et al. (2009) suggested that some hypomorphic mutations of TMEM67 do not lead to any neurologic impairment. Four additional patients with a more severe phenotype of Joubert syndrome-6 also had homozygous or compound heterozygous mutations (see, e.g., 609884.0011; 609884.0013; 609884.0019; 609884.0021-609884.0023). None of the patients with JBTS6 had truncating mutations on both alleles; all had at least 1 missense allele. Finally, the liver seems to be affected in most of the patients with TMEM67 mutations independently of the neurologic involvement, suggesting that liver disease is a specific feature resulting from TMEM67 mutations. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In the Wistar polycystic kidneys (Wpk) rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum, and hydrocephalus, Smith et al. (2006) refined the mapping of the Wpk locus and identified a missense mutation in the rat Tmem67 gene that was not present in the parental Wistar strain. </p><p>In the Wpk rat model of MKS3, Tammachote et al. (2009) reported functional defects of the connecting cilium in the eye that resulted in lack of formation of the outer segment, whereas infertile Wpk males developed spermatids with very short flagella that did not extend beyond the cell body. In Wpk renal collecting duct cysts, cilia were generally longer than normal, with additional evidence of cells with multiple primary cilia and centrosome overduplication. </p><p>Garcia-Gonzalo et al. (2011) found that Tmem67-null mice survived to birth without overt morphologic abnormalities, but died soon after. By embryonic day 18.5, Tmem67-null embryonic kidneys had developed cysts, and kidney tubules had fewer cilia than controls. Tmem67-null embryonic fibroblasts did not have ciliary defects, suggesting that Tmem67 has tissue-specific roles in ciliogenesis. Garcia-Gonzalo et al. (2011) also demonstrated that Tmem67 interacts with Tctn1 (609863) and Tctn2 (613846) and other proteins in a large complex localized to the transition zone between the ciliary axoneme and the basal body. </p><p>Adams et al. (2012) found that knockdown of Mks3 or the Flna ortholog in zebrafish resulted in similar phenotypes, including brain and body axis defects, cardiac edema, and otic placode and eye defects. Combined low doses of both Mks3 and Flna morpholinos increased both the incidence and severity of developmental defects. An Flna-null mouse strain showed similar defects. At embryonic day 13.5, male Flna hemizygous embryos were highly dysmorphic, with extensive disruption of ventricular zone of the neocortex and severe periventricular heterotopia. Basal body position was disrupted and neuroepithelial layer showed impaired ciliogenesis. </p><p>Abdelhamed et al. (2013) found that knockdown of Tmem67 in mice recapitulated the phenotypic variability of neurologic features seen in human ciliopathies. Two main phenotypic groups were recognized. Incipient congenic mice (F6 to F10) showed MKS-like features with variable neurologic abnormalities, including exencephaly and frontal/occipital encephalocele associated with the loss of primary cilia, diminished Shh signaling, and dorsalization of the caudal neural tube. These mutant mice also showed highly deregulated canonical Wnt/beta-catenin (CTNNB1; 116806) signaling associated with hyperactive DVL1 (601365) localized to the basal body: DVL1 is the downstream signaling modulator of Wnt pathways. Conversely, fully congenic mice (F greater than 10) had less variable neurodevelopmental features that were characteristic of JBTS, including cerebellar hypoplasia consistent with the molar tooth sign on imaging, and retention of abnormal bulbous cilia associated with neural tube ventralization. These mutant mice had low levels of deregulated canonical Wnt signaling associated with the loss of DVL1 localization to the basal body. Abdelhamed et al. (2013) suggested that modifier alleles likely determine the variation between MKS and JBTS caused by TMEM67 mutations. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>ALLELIC VARIANTS</strong>
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</span>
|
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<strong>28 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0001 MECKEL SYNDROME, TYPE 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TMEM67, 2-BP DEL, 383AC
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<br />
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SNP: rs386834200,
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ClinVar: RCV000001430
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an individual with Meckel syndrome type 3 (MKS3; 607361) from Oman, Smith et al. (2006) found a homozygous 2-bp deletion in exon 3 of the MKS3 gene, 383_384delAC, causing a frameshift beginning at his128 with premature stop at residue 140 (H128fsTer140). Each of the first-cousin parents was heterozygous for the mutation. The affected individual had occipital encephalocele, Dandy-Walker cysts, renal cystic dysplasia, hepatic developmental defects, and left-hand postaxial polydactyly. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0002 MECKEL SYNDROME, TYPE 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TMEM67, 1-BP DEL, 647A
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<br />
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SNP: rs386834204,
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ClinVar: RCV000001431
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Pakistani family with Meckel syndrome type 3 (MKS3; 607361), Smith et al. (2006) found that 2 affected sibs carried a homozygous 1-bp deletion (647delA) in exon 6 of the MKS3 gene. The deletion caused a frameshift beginning at glu216 of the protein, with premature termination at residue 221. The sibs had occipital encephalocele, renal cystic dysplasia, hepatic developmental defects, and midline cleft palate. </p><p>By immunohistochemical analysis, Dawe et al. (2007) found complete lack of meckelin expression in kidney from a patient with the 647delA mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 MECKEL SYNDROME, TYPE 3</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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TMEM67, IVS8, A-G, -2
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<br />
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|
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SNP: rs386834207,
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ClinVar: RCV000001432
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Pakistani family with Meckel syndrome type 3 (MKS3; 607361), Smith et al. (2006) found that a child with Meckel syndrome carried a homozygous splice site mutation, IVS8-2A-G, in the MKS3 gene. The child had occipital encephalocele, renal cystic dysplasia, and hepatic developmental defects. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 MECKEL SYNDROME, TYPE 3</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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|
|
TMEM67, GLN376PRO
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<br />
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|
|
SNP: rs137853106,
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|
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ClinVar: RCV000001434
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Pakistani patient with Meckel syndrome type 3 (MKS3; 607361), Smith et al. (2006) found a homozygous 1127A-C transversion in exon 11 of the MKS3 gene causing a missense protein change, Q376P. The patient had occipital encephalocele, renal cystic dysplasia, hepatic developmental defects, midline cleft palate, and epididymal cysts. </p><p>By immunohistochemical analysis, Dawe et al. (2007) found that the Q376P substitution in the N-terminal extracellular domain of meckelin resulted in lack of meckelin at the cell surface due to accumulation of the mutant protein in the endoplasmic reticulum. </p>
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<br />
|
|
</div>
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|
</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 MECKEL SYNDROME, TYPE 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM67, IVS15, G-A, +1
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|
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|
|
|
<br />
|
|
|
|
SNP: rs386834187,
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|
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|
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|
|
ClinVar: RCV000001435
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|
|
|
|
|
</span>
|
|
</div>
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|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Pakistani cases of Meckel syndrome type 3 (MKS3; 607361) in individuals related as double first cousins, Smith et al. (2006) found that the disorder was related to a homozygous splice site mutation in intron 15 of the MKS3 gene: IVS15+1G-A. One patient had occipital encephalocele, renal cystic dysplasia, and hepatic developmental defects; the other had the same 3 features as well as bilateral postaxial polydactyly. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 JOUBERT SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
COACH SYNDROME 1, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM67, TYR513CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137853107,
|
|
|
|
|
|
gnomAD: rs137853107,
|
|
|
|
|
|
ClinVar: RCV000001436, RCV000001437, RCV001851544, RCV004585980, RCV005049307
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Joubert Syndrome 6</em></strong></p><p>
|
|
In 2 sibs derived from pregnancies terminated at 30 weeks' and 28 weeks' gestation, respectively, because of abnormal posterior fossae and hyperechogenic, enlarged kidneys detected by ultrasound, Baala et al. (2007) found compound heterozygosity for 2 mutations in the MKS3 gene. A missense mutation in exon 15, tyr513 to cys (Y513C), was inherited from the father; a complex indel mutation (13-bp deletion encompassing the exon 22/intron 22 boundary replaced by 2 bp) was inherited from the mother. This 2315_2323+4del13insGG mutation (609884.0007) removed the donor splice site. Strong suspicion of Joubert syndrome in this family prompted a search for MKS3 mutations in patients with a typical form of the disorder and led to the establishment of a sixth locus for Joubert syndrome (JBTS6; 610688). </p><p><strong><em>COACH Syndrome 1</em></strong></p><p>
|
|
Doherty et al. (2010) identified the Y513C mutation in compound heterozygosity with another pathogenic TMEM67 mutation (see, e.g., I833T, 609884.0013) in 2 families with COACH syndrome-1 (COACH1; 216360), defined as Joubert syndrome with hepatic involvement. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 JOUBERT SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM67, 13-BP DEL, 2-BP INS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1554557920,
|
|
|
|
|
|
|
|
ClinVar: RCV000001433
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the complex indel mutation in the TMEM67 gene (13-bp deletion encompassing the exon 22/intron 22 boundary replaced by 2 bp) that was found in compound heterozygous state in a patient with Joubert syndrome-6 (JBTS6; 610688) by Baala et al. (2007), see 609884.0006. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 JOUBERT SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM67, IVS23+5G-C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs756686115,
|
|
|
|
|
|
gnomAD: rs756686115,
|
|
|
|
|
|
ClinVar: RCV000001438, RCV002512641
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 14-year-old Algerian girl, the child of consanguineous parents, with the molar tooth sign and superior vermian dysplasia (JBTS6; 610688), Baala et al. (2007) found homozygous MKS3 mutation near the donor splice site of intron 23 (IVS23+5G-C). Both parents and a healthy sister were heterozygous for the mutation. Sequencing of RNA transcript confirmed exon skipping from exons 22 to 24. This in-frame deletion predicted a protein lacking amino acids 775 to 813, which compose most of the putative coiled-coil domain of the protein. This patient had been reported by Romano et al. (2006). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 JOUBERT SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM67, IVS6+2T-G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199821258,
|
|
|
|
|
|
gnomAD: rs199821258,
|
|
|
|
|
|
ClinVar: RCV000001439, RCV000050199, RCV001698938, RCV001851545, RCV002281687, RCV004732520
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Baala et al. (2007) demonstrated compound heterozygosity for mutations in the MKS3 gene in a 7-year-old girl with a mild form of Joubert syndrome (JBTS6; 610688). The patient had been reported by Romano et al. (2006). Three MKS3 variations were found: on the maternal allele, a donor splice site mutation in intron 6 (IVS6+2T-G), and on the paternal allele, a missense mutation located in exon 16 (G545E; 609884.0010) and a mutation located at the last base of exon 21 (2341G-A; 609884.0010). Either of the mutations from the father could be deleterious. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 JOUBERT SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM67, GLY545GLU AND 2341G-A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs115563233, rs267607114,
|
|
|
|
|
|
gnomAD: rs115563233, rs267607114,
|
|
|
|
|
|
ClinVar: RCV000234818, RCV000723708, RCV001087450, RCV001163248, RCV001163249, RCV001163250, RCV002294093, RCV002512642, RCV003388643, RCV004732810, RCV004808544
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the in cis gly545-to-glu (G545E) and 2431G-A mutations in the TMEM67 gene that were found in compound heterozygous state in a patient with Joubert syndrome-6 (JBTS6; 610688) by Baala et al. (2007), see 609884.0009. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 MECKEL SYNDROME, TYPE 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
JOUBERT SYNDROME 6, INCLUDED<br />
|
|
RHYNS SYNDROME (1 patient), INCLUDED
|
|
</span>
|
|
</div>
|
|
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM67, ARG208TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137853108,
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|
|
|
|
|
gnomAD: rs137853108,
|
|
|
|
|
|
ClinVar: RCV000001442, RCV000001443, RCV000334857, RCV000468558, RCV000494327, RCV000723362, RCV002298428, RCV002490291, RCV003242959
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|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Meckel Syndrome 3</em></strong></p><p>
|
|
In affected fetuses from 3 unrelated families with Meckel syndrome type 3 (MKS3; 607361), Consugar et al. (2007) identified a heterozygous 622A-T transversion in exon 6 of the TMEM67 gene, resulting in an arg208-to-ter (R208X) substitution. All fetuses were compound heterozygous for R208X and another pathogenic mutation in the TMEM67 gene. </p><p><strong><em>Joubert Syndrome 6</em></strong></p><p>
|
|
In a German patient with Joubert syndrome-6 (JBTS6; 610688), Otto et al. (2009) identified compound heterozygosity for 2 mutations in the TMEM67 gene: R208X and I833T (609884.0013). The patient had end-stage renal failure at age 15, hepatic fibrosis, mental retardation, and cerebellar vermis atrophy. No ocular involvement was observed. </p><p><strong><em>RHYNS Syndrome</em></strong></p><p>
|
|
In a 38-year-old Italian man with RHYNS syndrome (RHYNS; 602152), originally reported by Di Rocco et al. (1997), Brancati et al. (2018) identified compound heterozygosity for the R208X mutation (c.622A-T, NM_153704.5) in the TMEM67 gene, and a c.1289A-G transition in exon 13, resulting in an asp430-to-gly (D430G; 609884.0026) substitution. His unaffected father and 2 unaffected brothers were heterozygous for the nonsense mutation, and his unaffected mother was heterozygous for the missense mutation. The D430G missense mutation was not found in the 1000 Genomes Project, ExAC, or gnomAD databases, whereas the nonsense mutation was present at very low frequency in the gnomAD database (49 of 277,178 alleles). Minigene assay using the pSPL3 vector system revealed absence of exon 13 after transfection with the D430G mutant; the authors suggested that the c.1289A-G mutation might result in exon 13 skipping, causing a frameshift and premature termination (Asp430SerfsTer9). </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0012 BARDET-BIEDL SYNDROME 14, MODIFIER OF</strong>
|
|
</span>
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|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
TMEM67, SER320CYS
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|
<br />
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|
|
SNP: rs111619594,
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|
|
|
gnomAD: rs111619594,
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|
|
|
|
ClinVar: RCV000001444, RCV000234830, RCV000725926, RCV001085857, RCV001158404, RCV001158405, RCV001158406, RCV001198570, RCV001333012, RCV003488318, RCV004528064
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|
</span>
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|
</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>In an 11-year-old female patient with Bardet-Biedl syndrome (see BBS14, 615991) Leitch et al. (2008) found heterozygosity for a complex mutation in the TMEM67 gene coding for a protein with 2 in cis changes, in addition to homozygosity for a truncating mutation of the CEP290 gene (610142.0013). One of the substitutions in the TMEM67 gene was predicted computationally to be benign, while the other, ser320 to cys (S320C), occurred at a highly conserved residue and was predicted to be pathogenic. The S320C mutation resulted in severe gastrulation movement defects in zebrafish embryos. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
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|
</div>
|
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|
</div>
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|
<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 COACH SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
JOUBERT SYNDROME 6, INCLUDED
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM67, ILE833THR
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|
<br />
|
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|
|
SNP: rs267607119,
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|
|
gnomAD: rs267607119,
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|
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|
|
|
ClinVar: RCV000001445, RCV000001446, RCV000821785, RCV000995902, RCV001310635, RCV001536092, RCV001804708, RCV003315221
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|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>COACH Syndrome 1</em></strong></p><p>
|
|
In 2 sibs originally reported by Verloes and Lambotte (1989) as having COACH syndrome (COACH1; 216360), Brancati et al. (2009) identified compound heterozygosity for 2 mutations in the TMEM67 gene: a 2498T-C transition in exon 24, resulting in an ile833-to-thr (I833T) substitution, and a splice site mutation in intron 24 (2556+1G-T; 609884.0014). An unrelated patient from Croatia was compound heterozygous for I833T and another splice site mutation in intron 2 (312+5G-A; 609884.0015). The phenotype in all patients was consistent with Joubert syndrome (JBTS6; 610688) with congenital hepatic fibrosis, indicating that COACH syndrome is a subtype of Joubert syndrome. </p><p>Doherty et al. (2010) identified the I833T mutation in compound heterozygosity with another pathogenic TMEM67 mutation (see, e.g., Y513C; 609884.0006) in 4 unrelated patients with COACH syndrome, which the authors defined as Joubert syndrome with liver involvement. </p><p><strong><em>Joubert Syndrome 6</em></strong></p><p>
|
|
In a patient diagnosed with Joubert syndrome, Otto et al. (2009) identified compound heterozygosity for 2 mutations in the TMEM67 gene: I833T and R208X (609884.0011). The patient had end-stage renal failure at age 16, liver fibrosis, mental retardation, and cerebellar vermis aplasia. Ocular involvement was not observed. </p><p>In a German girl with Joubert syndrome, Dafinger et al. (2011) identified compound heterozygosity for 2 mutations in the TMEM67 gene: I833T and pro358 to leu (P358L; 609884.0024). She also had a heterozygous 12-bp deletion in the KIF7 gene (3986del12; 611254.0008). The patient had mental retardation, molar tooth sign on brain MRI, ataxia, hypertelorism, low-set ears, coloboma, and elevated liver enzymes. </p>
|
|
</span>
|
|
</div>
|
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<div>
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|
<br />
|
|
</div>
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|
</div>
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|
<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 COACH SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
TMEM67, IVS24DS, G-T, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs786200867,
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|
|
|
|
|
|
|
ClinVar: RCV000001447, RCV000201565
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the splice site mutation in intron 24 of the TMEM67 gene (2556+1G-T) that was found in compound heterozygous state in patients with COACH syndrome (COACH1; 216360) by Brancati et al. (2009), see 609884.0013. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 COACH SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM67, IVS2DS, G-A, +5
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs786200868,
|
|
|
|
|
|
gnomAD: rs786200868,
|
|
|
|
|
|
ClinVar: RCV000001448, RCV001388801, RCV002496229
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the splice site mutation in intron 2 of the TMEM67 gene (312+5G-A) that was found in compound heterozygous state in patients with COACH syndrome (COACH1; 216360) by Brancati et al. (2009), see 609884.0013. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 COACH SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM67, PHE590SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607115,
|
|
|
|
|
|
gnomAD: rs267607115,
|
|
|
|
|
|
ClinVar: RCV000001449, RCV000201677, RCV001781164, RCV001851546, RCV005049308
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Italian brothers with COACH syndrome (COACH1; 216360) reported by Gentile et al. (1996), Brancati et al. (2009) identified compound heterozygosity for 2 mutations in the TMEM67 gene: a 1769T-C transition in exon 17, resulting in a phe590-to-ser (F590S) substitution, and a splice site mutation in intron 19 (1961-2A-C; 609884.0017). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 COACH SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM67, IVS19AS, A-C, -2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs758948621,
|
|
|
|
|
|
gnomAD: rs758948621,
|
|
|
|
|
|
ClinVar: RCV000001441, RCV000201576
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the splice mutation in intron 19 of the TMEM67 gene (1961-2A-C) that was found in compound heterozygous state in patients with COACH syndrome (COACH1; 216360) by Brancati et al. (2009), see 609884.0016. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 NEPHRONOPHTHISIS 11</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM67, GLY821SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607116,
|
|
|
|
|
|
|
|
ClinVar: RCV000001450, RCV000587331
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 sibs, born of consanguineous Turkish parents, with nephronophthisis and hepatic fibrosis (NPHP11; 613550), Otto et al. (2009) identified a homozygous 2461G-A transition in exon 24 of the TMEM67 gene, resulting in a gly821-to-ser (G821S) substitution in a highly conserved residue. The mutation was not found in 188 controls or in 147 ethnically matched controls. The patients developed end-stage renal disease between ages 9 and 14 years and had no neurologic abnormalities. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 NEPHRONOPHTHISIS 11</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
JOUBERT SYNDROME 6, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM67, CYS615ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs201893408,
|
|
|
|
|
|
gnomAD: rs201893408,
|
|
|
|
|
|
ClinVar: RCV000001451, RCV000001452, RCV000234823, RCV000283682, RCV000415055, RCV000479077, RCV000534533, RCV000623857, RCV000627004, RCV000763610, RCV001197497, RCV005041963
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Nephronophthisis 11</em></strong></p><p>
|
|
In a Turkish patient, born of consanguineous parents, with nephronophthisis-11 and hepatic fibrosis (NPHP11; 613550), Otto et al. (2009) identified a homozygous 1843T-C transition in exon 18 of the TMEM67 gene, resulting in a cys615-to-arg (C615R) substitution in a highly conserved residue. A German patient was also found to be homozygous for the mutation, and haplotype analysis indicated a common founder. The Turkish patient had end-stage renal failure at age 6, liver fibrosis, retinal degeneration, and mild cortical atrophy. The German patient had end-stage renal failure at age 6, liver fibrosis, Ehlers-Danlos syndrome, and no ocular or neurologic involvement. Another German patient with NPHP, liver fibrosis, strabismus, nystagmus, and mild 'statomotoric' retardation was found to be compound heterozygous for C615R and an 869G-T transversion in exon 8, resulting in a trp290-to-leu (W290L; 609884.0020) substitution. </p><p><strong><em>Joubert Syndrome 6</em></strong></p><p>
|
|
Otto et al. (2009) reported a patient with Joubert syndrome-6 (JBTS6; 610688) who was compound heterozygous for C615R and a 755T-C transition in exon 8 of the TMEM67 gene, resulting in a met252-to-thr (M252T; 609884.0023) substitution. The patient had end-stage renal failure at age 14, hepatic fibrosis, nystagmus, oculomotor apraxia, chorioretinal coloboma, ataxia, and psychomotor retardation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 NEPHRONOPHTHISIS 11</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM67, TRP290LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607117,
|
|
|
|
|
|
|
|
ClinVar: RCV000001453
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the trp290-to-leu (W290L) mutation in the TMEM67 gene that was found in compound heterozygous state in a patient with nephronophthisis-11 (NPHP11; 613550) by Otto et al. (2009), see 609884.0019. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 NEPHRONOPHTHISIS 11</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
JOUBERT SYNDROME 6, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM67, GLY821ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607116,
|
|
|
|
|
|
|
|
ClinVar: RCV000001454, RCV000001455
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a German patient with nephronophthisis-11 and hepatic fibrosis (NPHP11; 613550), Otto et al. (2009) identified a homozygous 2461G-C transversion in exon 24 of the TMEM67 gene, resulting in a gly821-to-arg (G821R) substitution. The patient developed end-stage renal failure at age 10 years, and also had anisocoria and psychomotor retardation, but normal brain MRI findings. An unrelated German patient with a more severe phenotype, consistent with Joubert syndrome-6 (JBTS6; 610688), was compound heterozygous for G821R and a 130C-T transition in exon 1, resulting in a gln44-to-ter (Q44X; 609884.0022) substitution. The patient with Joubert syndrome had end-stage renal failure at age 12, retinal degeneration, chorioretinal coloboma, ataxia, and cerebellar vermis aplasia. Liver involvement was not reported. Haplotype analysis of both patients indicated a common origin for the G821R mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 JOUBERT SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TMEM67, GLN44TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607118,
|
|
|
|
|
|
gnomAD: rs267607118,
|
|
|
|
|
|
ClinVar: RCV000001456, RCV001851547
|
|
|
|
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|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the gln44-to-ter (Q44X) mutation in the TMEM67 gene that was found in compound heterozygous state in a patient with Joubert syndrome-6 (JBTS6; 610688) by Otto et al. (2009), see 609884.0021. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0023 JOUBERT SYNDROME 6</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TMEM67, MET252THR
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<br />
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SNP: rs202149403,
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gnomAD: rs202149403,
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ClinVar: RCV000001457, RCV000234813, RCV000418247, RCV001389251, RCV002490292, RCV004689399, RCV004732521
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the met252-to-thr (M252T) mutation in the TMEM67 gene that was found in compound heterozygous state in a patient with Joubert syndrome-6 (JBTS6; 610688) by Otto et al. (2009), see 609884.0019. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0024 JOUBERT SYNDROME 6</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TMEM67, PRO358LEU
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<br />
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SNP: rs863225232,
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ClinVar: RCV000201590, RCV004528990
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the pro358-to-leu (P358L) mutation in the TMEM67 gene that was found in compound heterozygous state in a patient with Joubert syndrome-6 (JBTS6; 610688) by Dafinger et al. (2011), see 609884.0013. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0025 MECKEL SYNDROME 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TMEM67, 3-BP DEL, 2754CTT
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<br />
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SNP: rs786205126,
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ClinVar: RCV000049341
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient from a consanguineous family who presented with Meckel syndrome type 3 (MKS3; 607361) and cerebellar heterotopia, Adams et al. (2012) identified a homozygous 3-bp deletion, c.2754_2756delCTT, resulting in an in-frame deletion of phe919 (919delF) in the C-terminal cytoplasmic region of meckelin. The deletion abrogated the interaction of meckelin with filamin A (FLNA; 300017), resulting in aberrant hyperactivation of canonical Wnt signaling in patient fibroblasts compared with controls. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0026 RHYNS SYNDROME (1 patient)</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TMEM67, ASP430GLY
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<br />
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SNP: rs967792092,
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ClinVar: RCV000723363
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.1289A-G transition (c.1289A-G, NM_153704.5) in exon 13 of the TMEM67 gene, resulting in an asp430-to-gly (D430G) substitution, that was found in compound heterozygous state in a 38-year-old Italian man with RHYNS syndrome (602152) by Brancati et al. (2018), see 609884.0011. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0027 COACH SYNDROME 1</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TMEM67, GLY132ALA
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 20-year-old Korean man with COACH syndrome-1 (COACH1; 216360), Lee et al. (2017) identified compound heterozygous mutations in the TMEM67 gene: a c.395G-C transversion (c.395G-C, NM_153704.5) in exon 3, resulting in a gly132-to-ala (G132A) substitution in the cysteine-rich region, and a 1-bp deletion (c.2758delT; 609884.0028) in exon 26, resulting in a frameshift and premature termination (Tyr920ThrfsTer40). Both mutations occurred at highly conserved residues. The mutations were found by sequencing of the TMEM67 gene. The father was heterozygous for the mutation, but the mother was not tested. Transfection experiments in HEK293T cells showed that the c.2758delT mutation resulted in decreased stability and increased turnover of the protein, and the G132A mutation resulted in decreased mRNA expression, compared to wildtype. In TMEM67 Lee et al. (2017) also showed that in TMEM67 knockdown zebrafish with a hydrocephalus phenotype, injection with mutant morpholinos containing the G132A or c.2758delT mutations did not rescue the phenotype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0028 COACH SYNDROME 1</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TMEM67, 1-BP DEL, 2758T
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>For discussion of the 1-bp deletion (c.2758delT, NM_153704.5) in the TMEM67 gene that was found in compound heterozygous state in a patient with COACH syndrome-1 (COACH1; 216360) by Lee et al. (2017), see 609884.0027. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
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</h4>
|
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<div>
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
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Abdelhamed, Z. A., Wheway, G., Szymanska, K., Natarajan, S., Toomes, C., Inglehearn, C., Johnson, C. A.
|
|
<strong>Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects.</strong>
|
|
Hum. Molec. Genet. 22: 1358-1372, 2013.
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[PubMed: 23283079]
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[Full Text: https://doi.org/10.1093/hmg/dds546]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Adams, M., Simms, R. J., Abdelhamed, Z., Dawe, H. R., Szymanska, K., Logan, C. V., Wheway, G., Pitt, E., Gull, K., Knowles, M. A., Blair, E., Cross, S. H., Sayer, J. A., Johnson, C. A.
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<strong>A meckelin-filamin A interaction mediates ciliogenesis.</strong>
|
|
Hum. Molec. Genet. 21: 1272-1286, 2012.
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[PubMed: 22121117]
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[Full Text: https://doi.org/10.1093/hmg/ddr557]
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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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Baala, L., Romano, S., Khaddour, R., Saunier, S., Smith, U. M., Audollent, S., Ozilou, C., Faivre, L., Laurent, N., Foliguet, B., Munnich, A., Lyonnet, S., and 9 others.
|
|
<strong>The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome.</strong>
|
|
Am. J. Hum. Genet. 80: 186-194, 2007.
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[PubMed: 17160906]
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[Full Text: https://doi.org/10.1086/510499]
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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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Brancati, F., Camerota, L., Colao, E., Vega-Warner, V., Zhao, X., Zhang, R., Bottillo, I., Castori, M., Caglioti, A., Sangiuolo, F., Novelli, G., Perrotti, N., and 16 others.
|
|
<strong>Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome.</strong>
|
|
Europ. J. Hum. Genet. 26: 1266-1271, 2018.
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[PubMed: 29891882]
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[Full Text: https://doi.org/10.1038/s41431-018-0183-6]
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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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Brancati, F., Iannicelli, M., Travaglini, L., Mazzotta, A., Bertini, E., Boltshauser, E., D'Arrigo, S., Emma, F., Fazzi, E., Gallizzi, R., Gentile, M., Loncarevic, D., and 12 others.
|
|
<strong>MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement.</strong>
|
|
Hum. Mutat. 30: E432-E442, 2009. Note: Electronic Article.
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[PubMed: 19058225]
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[Full Text: https://doi.org/10.1002/humu.20924]
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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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Consugar, M. B., Kubly, V. J., Lager, D. J., Hommerding, C. J., Wong, W. C., Bakker, E., Gattone, V. H., II, Torres, V. E., Breuning, M. H., Harris, P. C.
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<strong>Molecular diagnostics of Meckel-Gruber syndrome highlights phenotypic differences between MKS1 and MKS3.</strong>
|
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Hum. Genet. 121: 591-599, 2007.
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[PubMed: 17377820]
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[Full Text: https://doi.org/10.1007/s00439-007-0341-3]
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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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Dafinger, C., Liebau, M. C., Elsayed, S. M., Hellenbroich, Y., Boltshauser, E., Korenke, G. C., Fabretti, F., Janecke, A. R., Ebermann, I., Nurnberg, G., Nurnberg, P., Zentgraf, H., Koerber, F., Addicks, K., Elsobky, E., Benzing, T., Schermer, B., Bolz, H. J.
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<strong>Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics.</strong>
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J. Clin. Invest. 121: 2662-2667, 2011.
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[PubMed: 21633164]
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[Full Text: https://doi.org/10.1172/JCI43639]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Dawe, H. R., Smith, U. M., Cullinane, A. R., Gerrelli, D., Cox, P., Badano, J. L., Blair-Reid, S., Sriram, N., Katsanis, N., Attie-Bitach, T., Afford, S. C., Copp, A. J., Kelly, D. A., Gull, K., Johnson, C. A.
|
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<strong>The Meckel-Gruber syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation.</strong>
|
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Hum. Molec. Genet. 16: 173-186, 2007.
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[PubMed: 17185389]
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[Full Text: https://doi.org/10.1093/hmg/ddl459]
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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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Di Rocco, M., Picco, P., Arslanian, A., Restagno, G., Perfumo, F., Buoncompagni, A., Gattorno, M., Borrone, C.
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<strong>Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): a new syndrome?</strong>
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Am. J. Med. Genet. 73: 1-4, 1997.
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[PubMed: 9375913]
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[Full Text: https://doi.org/10.1002/(sici)1096-8628(19971128)73:1<1::aid-ajmg1>3.0.co;2-y]
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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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Doherty, D., Parisi, M. A., Finn, L. S., Gunay-Aygun, M., Al-Mateen, M., Bates, D., Clericuzio, C., Demir, H., Dorschner, M., van Essen, A. J., Gahl, W. A., Gentile, M., and 11 others.
|
|
<strong>Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis).</strong>
|
|
J. Med. Genet. 47: 8-21, 2010.
|
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[PubMed: 19574260]
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[Full Text: https://doi.org/10.1136/jmg.2009.067249]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Garcia-Gonzalo, F. R., Corbit, K. C., Sirerol-Piquer, M. S., Ramaswami, G., Otto, E. A., Noriega, T. R., Seol, A. D., Robinson, J. F., Bennett, C. L., Josifova, D. J., Garcia-Verdugo, J. M., Katsanis, N., Hildebrandt, F., Reiter, J. F.
|
|
<strong>A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition.</strong>
|
|
Nature Genet. 43: 776-784, 2011.
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[PubMed: 21725307]
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[Full Text: https://doi.org/10.1038/ng.891]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Gentile, M., Di Carlo, A., Susca, F., Gambotto, A., Caruso, M. L., Panella, C., Vajro, P., Guanti, G.
|
|
<strong>COACH syndrome: report of two brothers with congenital hepatic fibrosis, cerebellar vermis hypoplasia, oligophrenia, ataxia, and mental retardation.</strong>
|
|
Am. J. Med. Genet. 64: 514-520, 1996.
|
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|
|
|
|
[PubMed: 8862632]
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|
|
[Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960823)64:3<514::AID-AJMG13>3.0.CO;2-O]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Lee, S.-H., Nam, T.-S., Li, W., Kim, J. H., Yoon, W., Choi, Y.-D., Kim, K.-H., Cai, H., Kim, M. J., Kim, C., Choy H. E., Kim, N., Chay, K. O., Kim, M.-K,, Choi, S.-Y.
|
|
<strong>Functional validation of novel MKS3/TMEM67 mutations in COACH syndrome.</strong>
|
|
Sci. Rep. 7: 10222, 2017. Note: Electronic Article.
|
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|
|
|
[PubMed: 28860541]
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[Full Text: https://doi.org/10.1038/s41598-017-10652-z]
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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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Leitch, C. C., Zaghloul, N. A., Davis, E. E., Stoetzel, C., Diaz-Font, A., Rix, S., Al-Fadhel, M., Lewis, R. A., Eyaid, W., Banin, E., Dollfus, H., Beales, P. L., Badano, J. L., Katsanis, N.
|
|
<strong>Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome.</strong>
|
|
Nature Genet. 40: 443-448, 2008. Note: Erratum: Nature Genet. 40: 927 only, 2008.
|
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|
[PubMed: 18327255]
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[Full Text: https://doi.org/10.1038/ng.97]
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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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Otto, E. A., Tory, K., Attanasio, M., Zhou, W., Chaki, M., Paruchuri, Y., Wise, E. L., Wolf, M. T. F., Utsch, B., Becker, C., Nurnberg, G., Nurnberg, P., Nayir, A., Saunier, S., Antignac, C., Hildebrandt, F.
|
|
<strong>Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).</strong>
|
|
J. Med. Genet. 46: 663-670, 2009.
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[PubMed: 19508969]
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[Full Text: https://doi.org/10.1136/jmg.2009.066613]
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Romano, S., Boddaert, N., Desguerre, I., Hubert, L., Salomon, R., Seidenwurm, D., Bahi-Buisson, N., Nabbout, R., Sonigo, P., Lyonnet, S., Brunelle, F., Munnich, A., de Lonlay, P.
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<strong>Molar tooth sign and superior vermian dysplasia: a radiological, clinical, and genetic study.</strong>
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Smith, U. R., Consugar, M., Tee, L. J., McKee, B. M., Maina, E. N., Whelan, S., Morgan, N. V., Goranson, E., Gissen, P., Lilliquist, S., Aligianis, I. A., Ward, C. J., and 19 others.
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<strong>The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and wpk rat.</strong>
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Nature Genet. 38: 191-196, 2006.
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Tammachote, R., Hommerding, C. J., Sinders, R. M., Miller, C. A., Czarnecki, P. G., Leightner, A. C., Salisbury, J. L., Ward, C. J., Torres, V. E., Gattone, V. H., II, Harris, P. C.
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<strong>Ciliary and centrosomal defects associated with mutation and depletion of the Meckel syndrome genes MKS1 and MKS3.</strong>
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Hum. Molec. Genet. 18: 3311-3323, 2009.
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Verloes, A., Lambotte, C.
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<strong>Further delineation of a syndrome of cerebellar vermis hypo/aplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis.</strong>
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Williams, C. L., Li, C., Kida, K., Inglis, P. N., Mohan, S., Semenec, L., Bialas, N. J., Stupay, R. M., Chen, N., Blacque, O. E., Yoder, B. K., Leroux, M. R.
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<strong>MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis.</strong>
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