5103 lines
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Entry
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- *602337 - RECEPTOR TYROSINE KINASE-LIKE ORPHAN RECEPTOR 2; ROR2
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*602337</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/602337">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000169071;t=ENST00000375708" 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=4920" 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=602337" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000169071;t=ENST00000375708" 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_001318204,NM_004560,XM_005252008,XM_005252009,XM_006717121,XM_017014762,XM_047423434,XM_047423435,XM_047423436,XM_047423437" 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_004560" 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=602337" 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=03822&isoform_id=03822_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/ROR2" 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/337467,9989696,11228721,19743898,62087888,90110767,119583202,119583203,119583204,119583205,119583206,120660404,530391155,530391157,578817504,970598266,1034665413,2217377341,2217377343,2217377345,2217377347,2462624843,2462624845,2462624847,2462624849,2462624851,2462624853,2462624855" 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/Q01974" 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=4920" 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=ENSG00000169071;t=ENST00000375708" 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=ROR2" 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=ROR2" 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+4920" 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/ROR2" 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:4920" 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/4920" 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=chr9&hgg_gene=ENST00000375708.4&hgg_start=91722601&hgg_end=91950228&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:10257" 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://medlineplus.gov/genetics/gene/ror2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=602337[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=602337[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/ROR2/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/ENSG00000169071" 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=ROR2" 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=ROR2" 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=ROR2" 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="http://www.LOVD.nl/ROR2" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ROR2&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/PA34629" 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:10257" 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/FBgn0010407.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:1347521" 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/ROR2#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:1347521" 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/4920/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/results?search_type=advanced&omia_id=001308,002223" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=4920" 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=WBGene00000289;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-060427-5" 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://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4920" 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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<div><a href="https://reactome.org/content/query?q=ROR2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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602337
|
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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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RECEPTOR TYROSINE KINASE-LIKE ORPHAN RECEPTOR 2; ROR2
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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">
|
|
NEUROTROPHIC TYROSINE KINASE, RECEPTOR-RELATED 2; NTRKR2
|
|
</span>
|
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</h4>
|
|
</div>
|
|
</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=ROR2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ROR2</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/9/300?start=-3&limit=10&highlight=300">9q22.31</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:91722601-91950228&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'})">9:91,722,601-91,950,228</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=113000,268310" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/9/300?start=-3&limit=10&highlight=300">
|
|
9q22.31
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Brachydactyly, type B1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/113000"> 113000 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
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</td>
|
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|
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|
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</tr>
|
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|
|
|
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|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Robinow syndrome, autosomal recessive
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/268310"> 268310 </a>
|
|
|
|
</span>
|
|
</td>
|
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<td>
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<p>The receptor tyrosine kinases (RTK), including ROR1, are a large superfamily of transmembrane glycoproteins that function as cell surface receptors. RTKs play a role in the control of most basic cellular processes including cell proliferation, differentiation, migration and metabolism (summary by <a href="#1" class="mim-tip-reference" title="Afzal, A. R., Jeffery, S. <strong>One gene, two phenotypes: ROR2 mutations in autosomal recessive Robinow syndrome and autosomal dominant brachydactyly type B.</strong> Hum. Mutat. 22: 1-11, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12815588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12815588</a>] [<a href="https://doi.org/10.1002/humu.10233" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12815588">Afzal and Jeffery, 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12815588" 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 degenerate PCR using primers based on conserved regions of NTRK1 (<a href="/entry/191315">191315</a>) and NTRK2 (<a href="/entry/600456">600456</a>), <a href="#15" class="mim-tip-reference" title="Masiakowski, P., Carroll, R. D. <strong>A novel family of cell surface receptors with tyrosine kinase-like domain.</strong> J. Biol. Chem. 267: 26181-26190, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1334494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1334494</a>]" pmid="1334494">Masiakowski and Carroll (1992)</a> identified 2 additional members of the TRK family, NTRKR1 (ROR1; <a href="/entry/602336">602336</a>) and NTRKR2, also called ROR2. <a href="#15" class="mim-tip-reference" title="Masiakowski, P., Carroll, R. D. <strong>A novel family of cell surface receptors with tyrosine kinase-like domain.</strong> J. Biol. Chem. 267: 26181-26190, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1334494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1334494</a>]" pmid="1334494">Masiakowski and Carroll (1992)</a> showed that NTRKR2 encodes a predicted 943-amino acid protein with in vitro protein kinase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1334494" 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>Receptor tyrosine kinases often have critical roles in particular cell lineages by initiating signal cascades in those lineages. Many lineage-restricted receptor tyrosine kinases were initially identified as 'orphans' homologous to known receptors, and only subsequently used to identify their unknown growth factors. <a href="#7" class="mim-tip-reference" title="DeChiara, T. M., Kimble, R. B., Poueymirou, W. T., Rojas, J., Masiakowski, P., Valenzuela, D. M., Yancopoulos, G. D. <strong>Ror2, encoding a receptor-like tyrosine kinase, is required for cartilage and growth plate development.</strong> Nature Genet. 24: 271-274, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10700181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10700181</a>] [<a href="https://doi.org/10.1038/73488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10700181">DeChiara et al. (2000)</a> identified one such orphan, encoded by Ror2. They reported that disruption of mouse Ror2 leads to profound skeletal abnormalities, with essentially all endochondrally derived bones foreshortened or misshapen, albeit to differing degrees. Further, they found that Ror2 is selectively expressed in the chondrocytes of all developing cartilage anlagen, where it is essential during initial growth and patterning, as well as subsequently in the proliferating chondrocytes of mature growth plates, where it is required for normal expansion. Thus, Ror2 encodes a receptor-like tyrosine kinase that is selectively expressed in, and particularly important for, the chondrocyte lineage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10700181" 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 radiation hybrid mapping between D9S1842 and D9S196 on 2 independent panels, <a href="#8" class="mim-tip-reference" title="Deloukas, P., Schuler, G. D., Gyapay, G., Beasley, E. M., Soderlund, C., Rodriguez-Tome, P., Hui, L., Matise, T. C., McKusick, K. B., Beckmann, J. S., Bentolila, S., Bihoreau, M.-T., and 53 others. <strong>A physical map of 30,000 human genes.</strong> Science 282: 744-746, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9784132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9784132</a>] [<a href="https://doi.org/10.1126/science.282.5389.744" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9784132">Deloukas et al., 1998</a> mapped the ROR2 gene to chromosome 9q22. By FISH analysis, <a href="#20" class="mim-tip-reference" title="Oldridge, M., Fortuna, A. M., Maringa, M., Propping, P., Mansour, S., Pollitt, C., DeChiara, T. M., Kimble, R. B., Valenzuela, D. M., Yancopoulos, G. D., Wilkie, A. O. M. <strong>Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.</strong> Nature Genet. 24: 275-278, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10700182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10700182</a>] [<a href="https://doi.org/10.1038/73495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10700182">Oldridge et al., 2000</a> confirmed localization of the ROR2 gene to chromosome 9q22. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9784132+10700182" 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>The mouse Ror2 gene maps to chromosome 13, in a region of conserved synteny with human chromosome 9q (<a href="#19" class="mim-tip-reference" title="Oishi, I., Takeuchi, S., Hashimoto, R., Nagabukuro, A., Ueda, T., Liu, Z.-J., Hatta, T., Akira, S., Matsuda, Y., Yamamura, H., Otani, H., Minami, Y. <strong>Spatio-temporally regulated expression of receptor tyrosine kinases, mRor1, mRor2, during mouse development: implications in development and function of the nervous system.</strong> Genes Cells 4: 41-56, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10231392/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10231392</a>] [<a href="https://doi.org/10.1046/j.1365-2443.1999.00234.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10231392">Oishi et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10231392" 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 mouse proteins, <a href="#16" class="mim-tip-reference" title="Mikels, A. J., Nusse, R. <strong>Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context.</strong> PLoS Biol. 4: e115, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16602827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16602827</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16602827[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/10.1371/journal.pbio.0040115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16602827">Mikels and Nusse (2006)</a> demonstrated that Ror2 is a receptor for Wnt5a (<a href="/entry/164975">164975</a>) and serves to inhibit canonical Wnt signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16602827" 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 immunostaining, <a href="#31" class="mim-tip-reference" title="Zhang, C., Brunt, L., Ono, Y., Rogers, S., Scholpp, S. <strong>Cytoneme-mediated transport of active Wnt5b-Ror2 complexes in zebrafish.</strong> Nature 625: 126-133, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38123680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38123680</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38123680[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/s41586-023-06850-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38123680">Zhang et al. (2024)</a> showed that ligand wnt5b (<a href="/entry/606361">606361</a>) and its plasma membrane-bound receptor ror2 were expressed and colocalized on cell protrusions in PAC2 zebrafish fibroblasts. Overexpression and knockout analyses in PAC2 cells revealed that wnt5b and ror2 formed a ligand-receptor complex and were transported from producing cells to receiving cells. During transport, wnt5b and the N-terminal part of ror2 faced the extracellular side of the membrane and were loaded together on signaling filopodia that the authors referred to as cytonemes, and the ligand-receptor complex was taken up by dynamin-dependent endocytosis into receiving cells via the cytonemes. The same transport was seen in zebrafish embryos, and further analysis with living zebrafish embryos indicated that ror2 bound to wnt5b with high affinity at the plasma membrane of producing cells, and that structural integrity of the complex was maintained during both transportation and subsequent uptake into receiving cells. Knockout and overexpression analyses in zebrafish revealed that wnt5b-ror2 regulated cytoneme formation, as binding between wnt5b and ror2 triggered the Wnt-planar cell polarity (PCP) signaling pathway, which induced long wnt5b-ror2-bearing cytonemes to facilitate spreading of wnt5b and ror2. The cytonemes were stabilized through irsp53 (BAIAP2; <a href="/entry/605475">605475</a>) and Wnt-JNK (see <a href="/entry/601158">601158</a>) signaling, and ror2 directly delivered by cytonemes was required for paracrine Wnt-JNK activation, indicating that the transferred wnt5b-ror2 complex maintained its activity in target cells. In addition to activating JNK signaling, paracrine ror2 also repressed beta-catenin (CTNNB1; <a href="/entry/116806">116806</a>) signaling, thereby influencing convergence and extension in zebrafish development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38123680" 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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Inherited limb malformations provide a valuable resource for identification of genes involved in limb development (<a href="#11" class="mim-tip-reference" title="Innis, J. W., Mortlock, D. P. <strong>Limb development: molecular dysmorphology is at hand!</strong> Clin. Genet. 53: 337-348, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9660051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9660051</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1998.tb02744.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9660051">Innis and Mortlock, 1998</a>; <a href="#14" class="mim-tip-reference" title="Manouvrier-Hanu, S., Holder-Espinasse, M., Lyonnet, S. <strong>Genetics of limb anomalies in humans.</strong> Trends Genet. 15: 409-417, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10498937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10498937</a>] [<a href="https://doi.org/10.1016/s0168-9525(99)01823-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10498937">Manouvrier-Hanu et al., 1999</a>). Brachydactyly type B (BDB1; <a href="/entry/113000">113000</a>), an autosomal dominant disorder, is the most severe of the brachydactylies and is characterized by terminal deficiency of the fingers and toes. In the typical form of BDB, the thumbs and big toes are spared, sometimes with broadening or partial duplication. The BDB1 locus was mapped to 9q22 within an interval of 7.5 cM (<a href="#9" class="mim-tip-reference" title="Gong, Y., Chitayat, D., Kerr, B., Chen, T., Babul-Hirji, R., Pal, A., Reiss, M., Warman, M. L. <strong>Brachydactyly type B: clinical description, genetic mapping to chromosome 9q, and evidence for a shared ancestral mutation.</strong> Am. J. Hum. Genet. 64: 570-577, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9973295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9973295</a>] [<a href="https://doi.org/10.1086/302249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9973295">Gong et al., 1999</a>; <a href="#21" class="mim-tip-reference" title="Oldridge, M., Temple, I. K. Santos, H. G., Gibbons, R. J., Mustafa, Z., Chapman, K. E., Loughlin, J., Wilkie, A. O. M. <strong>Brachydactyly type B: linkage to chromosome 9q22 and evidence for genetic heterogeneity.</strong> Am. J. Hum. Genet. 64: 578-585, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9973296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9973296</a>] [<a href="https://doi.org/10.1086/302255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9973296">Oldridge et al., 1999</a>). <a href="#20" class="mim-tip-reference" title="Oldridge, M., Fortuna, A. M., Maringa, M., Propping, P., Mansour, S., Pollitt, C., DeChiara, T. M., Kimble, R. B., Valenzuela, D. M., Yancopoulos, G. D., Wilkie, A. O. M. <strong>Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.</strong> Nature Genet. 24: 275-278, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10700182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10700182</a>] [<a href="https://doi.org/10.1038/73495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10700182">Oldridge et al. (2000)</a> identified distinct heterozygous mutations (2 nonsense, 1 frameshift) within a 7-amino acid segment of the 943-amino acid ROR2 protein, all of which predicted truncation of the intracellular portion of the protein immediately after the tyrosine kinase domain. The localized nature of these mutations suggested that they confer a specific gain of function. <a href="#20" class="mim-tip-reference" title="Oldridge, M., Fortuna, A. M., Maringa, M., Propping, P., Mansour, S., Pollitt, C., DeChiara, T. M., Kimble, R. B., Valenzuela, D. M., Yancopoulos, G. D., Wilkie, A. O. M. <strong>Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.</strong> Nature Genet. 24: 275-278, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10700182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10700182</a>] [<a href="https://doi.org/10.1038/73495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10700182">Oldridge et al. (2000)</a> obtained further evidence for this by demonstrating that 2 patients heterozygous for 9q22 deletions including ROR2 did not exhibit BDB. Expression of the mouse ortholog, Ror2, early in limb development indicated that BDB arises as a primary defect of skeletal patterning. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10498937+9973295+9973296+9660051+10700182" 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 5 families with BDB, <a href="#24" class="mim-tip-reference" title="Schwabe, G. C., Tinschert, S., Buschow, C., Meinecke, P., Wolff, G., Gillessen-Kaesbach, G., Oldridge, M., Wilkie, A. O. M., Komec, R., Mundlos, S. <strong>Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.</strong> Am. J. Hum. Genet. 67: 822-831, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10986040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10986040</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10986040[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/10.1086/303084" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10986040">Schwabe et al. (2000)</a> found 4 novel mutations in ROR2: 2 frameshifts (see, e.g., <a href="#0008">602337.0008</a>), 1 splice mutation, and 1 nonsense mutation. The mutations predicted truncation of the protein within 2 distinct regions immediately before and after the tyrosine kinase (TK) domain, resulting in a complete or partial loss of the intracellular portion of the protein. Patients with the distal mutations had a more severe phenotype than did those with the proximal mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10986040" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Bacchelli, C., Wilson, L. C., Cook, J. A., Winter, R. M., Goodman, F. R. <strong>ROR2 is mutated in hereditary brachydactyly with nail dysplasia, but not in Sorsby syndrome. (Letter)</strong> Clin. Genet. 64: 263-265, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12919145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12919145</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00139.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12919145">Bacchelli et al. (2003)</a> reviewed 4 affected members of a large Welsh family with a dominantly inherited form of isolated brachydactyly first described by <a href="#22" class="mim-tip-reference" title="Schott, G. D. <strong>Hereditary brachydactyly with nail dysplasia.</strong> J. Med. Genet. 15: 119-122, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/641944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">641944</a>] [<a href="https://doi.org/10.1136/jmg.15.2.119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="641944">Schott (1978)</a>, who designated it hereditary brachydactyly with nail dysplasia. Although <a href="#23" class="mim-tip-reference" title="Schott, G. D. <strong>Hereditary brachydactyly with nail dysplasia. (Letter)</strong> J. Med. Genet. 16: 236 only, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/469906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">469906</a>] [<a href="https://doi.org/10.1136/jmg.16.3.236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="469906">Schott (1979)</a> recognized that the external and radiologic appearance of the affected individuals' hands were very similar to brachydactyly type B1, he maintained that the disorder could be distinguished from BDB1 by the complete absence of foot involvement. <a href="#4" class="mim-tip-reference" title="Bacchelli, C., Wilson, L. C., Cook, J. A., Winter, R. M., Goodman, F. R. <strong>ROR2 is mutated in hereditary brachydactyly with nail dysplasia, but not in Sorsby syndrome. (Letter)</strong> Clin. Genet. 64: 263-265, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12919145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12919145</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00139.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12919145">Bacchelli et al. (2003)</a> found, however, that in addition to hand anomalies typical of BDB, affected members of the Welsh kindred had subtle but definite foot involvement, including mild shortening of the second to fifth toes, occasional nail hypoplasia, and clinically evident distal symphalangism. Facial appearance was also typical of BDB, including a short philtrum and a prominent nose with a high bridge and bulbous tip. Direct sequencing of ROR2 demonstrated a nonsense mutation (W749X; <a href="#0009">602337.0009</a>). A heterozygous G-to-A transition in exon 9 (2247G-A) was responsible for the premature stop. The same nonsense change in codon 749 had been reported in a German family with typical BDB, although the underlying base change in that family was different (2246G-A). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=469906+641944+12919145" 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 large Turkish family with a mild BDB1 phenotype, known to be negative for mutation in the NOG (<a href="/entry/602991">602991</a>) and GDF5 (<a href="/entry/601146">601146</a>) genes, <a href="#12" class="mim-tip-reference" title="Kjaer, K. W., Tiner, M., Cingoz, S., Karatosun, V., Tommerup, N., Mundlos, S., Gunal, I. <strong>A novel subtype of distal symphalangism affecting only the 4th finger. (Letter)</strong> Am. J. Med. Genet. 149A: 1571-1573, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19533773/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19533773</a>] [<a href="https://doi.org/10.1002/ajmg.a.32905" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19533773">Kjaer et al. (2009)</a> identified a heterozygous truncating mutation in the ROR2 gene (<a href="#0013">602337.0013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19533773" 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>Robinow Syndrome, Autosomal Recessive 1</em></strong></p><p>
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autosomal recessive Robinow syndrome-1 (RRS1; <a href="/entry/268310">268310</a>) is a severe skeletal dysplasia with generalized shortening of the bones of the limbs, segmental defects of the spine, brachydactyly, and a dysmorphic facial appearance. <a href="#2" class="mim-tip-reference" title="Afzal, A. R., Rajab, A., Fenske, C. D., Oldridge, M., Elanko, N., Ternes-Pereira, E., Tuysuz, B., Murday, V. A., Patton, M. A., Wilkie, A. O. M., Jeffery, S. <strong>Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2.</strong> Nature Genet. 25: 419-422, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10932186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10932186</a>] [<a href="https://doi.org/10.1038/78107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10932186">Afzal et al. (2000)</a> mapped the gene mutant in this disorder to 9q22, a region that overlaps the locus for autosomal dominant brachydactyly type B. The identification of ROR2, encoding a receptor tyrosine kinase, as the gene mutated in brachydactyly type B and in the mesomelic dwarfing in mice homozygous for insertions in the Ror2 gene, made this gene a candidate for autosomal recessive Robinow syndrome. <a href="#2" class="mim-tip-reference" title="Afzal, A. R., Rajab, A., Fenske, C. D., Oldridge, M., Elanko, N., Ternes-Pereira, E., Tuysuz, B., Murday, V. A., Patton, M. A., Wilkie, A. O. M., Jeffery, S. <strong>Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2.</strong> Nature Genet. 25: 419-422, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10932186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10932186</a>] [<a href="https://doi.org/10.1038/78107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10932186">Afzal et al. (2000)</a> reported homozygous missense mutations (e.g., <a href="#0005">602337.0005</a>) in both intracellular and extracellular domains of ROR2 in affected individuals from 3 unrelated consanguineous families, and a Q502X mutation (<a href="#0004">602337.0004</a>) that removed the tyrosine kinase domain in all subsequent 3-prime regions of the gene in 14 patients from 7 families from Oman. The nature of these mutations suggested that this form of Robinow syndrome is caused by loss of ROR2 activity. Identification of mutations from 3 distinct domains (containing frizzled-like, kringle, and tyrosine kinase motifs) indicated that these are all essential for ROR2 function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10932186" 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="#30" class="mim-tip-reference" title="van Bokhoven, H., Celli, J., Kayserili, H., van Beusekom, E., Balci, S., Brussel, W., Skovby, F., Kerr, B., Percin, E. F., Akarsu, N., Brunner, H. G. <strong>Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome.</strong> Nature Genet. 25: 423-426, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10932187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10932187</a>] [<a href="https://doi.org/10.1038/78113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10932187">Van Bokhoven et al. (2000)</a> also mapped autosomal recessive Robinow syndrome to chromosome 9q21-q22 and detected homozygous ROR2 mutations in a cohort of 10 families of Turkish descent and 1 of Pakistani descent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10932187" 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="#28" class="mim-tip-reference" title="Tufan, F., Cefle, K., Turkmen, S., Turkmen, A., Zorba, U., Dursun, M., Ozturk, S., Palanduz, S., Ecder, T., Mundlos, S., Horn, D. <strong>Clinical and molecular characterization of two adults with autosomal recessive Robinow syndrome.</strong> Am. J. Med. Genet. 136A: 185-189, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15952209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15952209</a>] [<a href="https://doi.org/10.1002/ajmg.a.30785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15952209">Tufan et al. (2005)</a> reported 2 patients with autosomal recessive Robinow syndrome and mutations in the ROR2 gene: one homozygous for a deletion (<a href="#0010">602337.0010</a>) and the other compound heterozygous for a missense (R184C; <a href="#0005">602337.0005</a>) and a nonsense (R119X; <a href="#0011">602337.0011</a>) mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15952209" 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 bioinformatic analysis and immunoprecipitation studies, <a href="#6" class="mim-tip-reference" title="Chen, Y., Bellamy, W. P., Seabra, M. C., Field, M. C., Ali, B. R. <strong>ER-associated protein degradation is a common mechanism underpinning numerous monogenic diseases including Robinow syndrome.</strong> Hum. Molec. Genet. 14: 2559-2569, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16049033/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16049033</a>] [<a href="https://doi.org/10.1093/hmg/ddi259" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16049033">Chen et al. (2005)</a> showed that endoplasmic reticulum (ER) retention was the mechanism underlying Robinow syndrome-1. Specifically, mutant alleles of ROR2, including the R184C mutation, that are associated with autosomal recessive Robinow syndrome were retained within the ER, whereas wildtype and nonpathogenic alleles were exported to the plasma membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16049033" 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 an unrelated boy and girl with autosomal recessive Robinow syndrome, <a href="#3" class="mim-tip-reference" title="Ali, B. R., Jeffery, S., Patel, N., Tinworth, L. E., Meguid, N., Patton, M. A., Afzal, A. R. <strong>Novel Robinow syndrome causing mutations in the proximal region of the frizzled-like domain of ROR2 are retained in the endoplasmic reticulum.</strong> Hum. Genet. 122: 389-395, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17665217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17665217</a>] [<a href="https://doi.org/10.1007/s00439-007-0409-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17665217">Ali et al. (2007)</a> identified homozygosity for different missense mutations, respectively, located in the proximal region of the extracellular frizzled-like domain of the ROR2 gene. In studies in HeLa cells, the authors demonstrated that the mutated proteins were retained in the ER and failed to reach the plasma membrane. Noting the clustering of Robinow-causing mutations in the extracellular frizzled-like cysteine-rich domain of ROR2, <a href="#3" class="mim-tip-reference" title="Ali, B. R., Jeffery, S., Patel, N., Tinworth, L. E., Meguid, N., Patton, M. A., Afzal, A. R. <strong>Novel Robinow syndrome causing mutations in the proximal region of the frizzled-like domain of ROR2 are retained in the endoplasmic reticulum.</strong> Hum. Genet. 122: 389-395, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17665217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17665217</a>] [<a href="https://doi.org/10.1007/s00439-007-0409-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17665217">Ali et al. (2007)</a> suggested that there is a stringent requirement for the correct folding of this domain prior to export of ROR2 from the ER. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17665217" 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 2 sib pairs with Robinow syndrome from the same extended family, <a href="#5" class="mim-tip-reference" title="Brunetti-Pierri, N., del Gaudio, D., Peters, H., Justino, H., Ott, C.-E., Mundlos, S., Bacino, C. A. <strong>Robinow syndrome: phenotypic variability in a family with a novel intragenic ROR2 mutation.</strong> Am. J. Med. Genet. 146A: 2804-2809, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18831060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18831060</a>] [<a href="https://doi.org/10.1002/ajmg.a.32530" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18831060">Brunetti-Pierri et al. (2008)</a> identified homozygosity for a deletion encompassing exons 6 and 7 of the ROR2 gene (<a href="#0012">602337.0012</a>); all 4 unaffected parents were heterozygous for the deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18831060" 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="#29" class="mim-tip-reference" title="van Bokhoven, H., Brunner, H. G. <strong>Splitting p63.</strong> Am. J. Hum. Genet. 71: 1-13, 2002. Note: Erratum: Am. J. Hum. Genet. 72: 779 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12037717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12037717</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12037717[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/10.1086/341450" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12037717">Van Bokhoven and Brunner (2002)</a> pointed out that the mechanism of divergent phenotypes of disorders caused by allelic mutations is illustrated by dominant BDB and recessive Robinow syndrome which are caused, respectively, by gain-of-function and loss-of-function mutations in the ROR2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12037717" 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="Afzal, A. R., Jeffery, S. <strong>One gene, two phenotypes: ROR2 mutations in autosomal recessive Robinow syndrome and autosomal dominant brachydactyly type B.</strong> Hum. Mutat. 22: 1-11, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12815588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12815588</a>] [<a href="https://doi.org/10.1002/humu.10233" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12815588">Afzal and Jeffery (2003)</a> presented a compilation of the defects in the ROR2 gene leading to autosomal recessive Robinow syndrome and autosomal dominant BDB and discussed possible genotype-phenotype correlations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12815588" 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>Recessive Robinow Syndrome with Severe Malformations of the Hands and Feet</em></strong></p><p>
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In a large Turkish kindred in which many members over at least 6 generations had dominant BDB1, <a href="#24" class="mim-tip-reference" title="Schwabe, G. C., Tinschert, S., Buschow, C., Meinecke, P., Wolff, G., Gillessen-Kaesbach, G., Oldridge, M., Wilkie, A. O. M., Komec, R., Mundlos, S. <strong>Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.</strong> Am. J. Hum. Genet. 67: 822-831, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10986040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10986040</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10986040[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/10.1086/303084" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10986040">Schwabe et al. (2000)</a> described a man, born of consanguineous parents with BDB1, who was homozygous for a 5-bp deletion proximal to the TK domain, resulting in frameshift at the arg441 residue (<a href="#0008">602337.0008</a>). His phenotype resembled an extreme form of brachydactyly, with extensive aplasia/hypoplasia of the phalanges and metacarpals/metatarsals and absence of nails. In addition, he had vertebral anomalies, brachymelia anomalies (short arms), and a ventricular septal defect--features reminiscent of Robinow syndrome. The phenotype in this patient suggested a specific mutation effect that cannot be explained by simple haploinsufficiency and that is distinct from that in Robinow syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10986040" 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="#26" class="mim-tip-reference" title="Schwarzer, W., Witte, F., Rajab, A., Mundlos, S., Stricker, S. <strong>A gradient of ROR2 protein stability and membrane localization confers brachydactyly type B or Robinow syndrome phenotypes.</strong> Hum. Molec. Genet. 18: 4013-4021, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19640924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19640924</a>] [<a href="https://doi.org/10.1093/hmg/ddp345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19640924">Schwarzer et al. (2009)</a> reported an R441X mutation in the ROR2 gene (<a href="#0014">602337.0014</a>) in an Omani patient exhibiting features of Robinow syndrome in conjunction with complex, symmetric brachy-syn-polydactyly of the hands and oligodactyly of the feet with absent toes 2 to 4. The Omani parents were healthy, had no features of Robinow syndrome or BDB1, and were distantly related by mothers of the same tribal background. The R441X mutation was located at the same position as the frameshift mutation at arg441. Transfection experiments with a series of mutant transcripts revealed that recessive Robinow syndrome (RRS) mutant proteins, such as Q502X and W720X (<a href="#0006">602337.0006</a>), were less abundant and retained intracellularly, whereas BDB1 mutants, such as W749X, were stable and predominantly located at the cell membrane. Both the frameshift mutation and the R441X mutation showed an intermediate pattern with membrane localization but also high ER retention, although the R441X mutant had a significantly lower total protein level and less membrane-associated protein than the frameshift mutant. There was a correlation between the severity of BDB1, the location of the mutation, and the amount of membrane-associated ROR2. Membrane protein fraction quantification revealed a gradient of distribution and stability correlating with the clinical phenotypes. This gradual model was confirmed by crossing mouse models for RRS and BDB1, yielding double heterozygous animals that exhibited an intermediate phenotype. <a href="#26" class="mim-tip-reference" title="Schwarzer, W., Witte, F., Rajab, A., Mundlos, S., Stricker, S. <strong>A gradient of ROR2 protein stability and membrane localization confers brachydactyly type B or Robinow syndrome phenotypes.</strong> Hum. Molec. Genet. 18: 4013-4021, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19640924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19640924</a>] [<a href="https://doi.org/10.1093/hmg/ddp345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19640924">Schwarzer et al. (2009)</a> proposed a model in which the phenotypic outcome of ROR2 mutations is determined by 2 threshold levels: the degree of protein retention/degradation determines the RRS phenotype, whereas the amount of mutant protein reaching the plasma membrane determines the severity of the BDB1 phenotype. A mixture of both effects can result in a balance of gain of function and loss of function and, consequently, an overlapping phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19640924" 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="#27" class="mim-tip-reference" title="Takeuchi, S., Takeda, K., Oishi, I., Nomi, M., Ikeya, M., Itoh, K., Tamura, S., Ueda, T., Hatta, T., Otani, H., Terashima, T., Takada, S., Yamamura, H., Akira, S., Minami, Y. <strong>Mouse Ror2 receptor tyrosine kinase is required for the heart development and limb formation.</strong> Genes Cells 5: 71-78, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10651906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10651906</a>] [<a href="https://doi.org/10.1046/j.1365-2443.2000.00300.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10651906">Takeuchi et al. (2000)</a> generated mice with a mutation in the Ror2 gene and observed that homozygous mutant mice died just after birth, exhibiting dwarfism, severe cyanosis, and short limbs and tails. Whole-mount in situ hybridization analysis showed that Ror2 is expressed in the branchial arches, heart, and limb/tailbuds, in addition to the developing nervous system. The Ror2-deficient mice had cardiac septal defects and skeletal abnormalities, including shorter limbs, vertebrae, and facial structure, with a particular defect in their distal portions. <a href="#27" class="mim-tip-reference" title="Takeuchi, S., Takeda, K., Oishi, I., Nomi, M., Ikeya, M., Itoh, K., Tamura, S., Ueda, T., Hatta, T., Otani, H., Terashima, T., Takada, S., Yamamura, H., Akira, S., Minami, Y. <strong>Mouse Ror2 receptor tyrosine kinase is required for the heart development and limb formation.</strong> Genes Cells 5: 71-78, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10651906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10651906</a>] [<a href="https://doi.org/10.1046/j.1365-2443.2000.00300.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10651906">Takeuchi et al. (2000)</a> concluded that Ror2 plays essential roles in the development of the heart and in limb/tail formation, in particular cardiac septal formation and ossification of distal portions of limbs and tails. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10651906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Nomi, M., Oishi, I., Kani, S., Suzuki, H., Matsuda, T., Yoda, A., Kitamura, M., Itoh, K., Takeuchi, S., Takeda, K., Akira, S., Ikeya, M., Takada, S., Minami, Y. <strong>Loss of mRor1 enhances the heart and skeletal abnormalities in mRor2-deficient mice: redundant and pleiotropic functions of mRor1 and mRor2 receptor tyrosine kinases.</strong> Molec. Cell. Biol. 21: 8329-8335, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11713269/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11713269</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11713269[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/10.1128/MCB.21.24.8329-8335.2001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11713269">Nomi et al. (2001)</a> bred double-mutant mice lacking both the Ror1 and Ror2 genes. Using skeletal preparations, they observed that Ror1/Ror2 double-mutant mice showed skeletal abnormalities more severe than those seen in Ror2 mutant mice, including a sternal defect, dysplasia of the symphysis of the pubic bone. Histologic analysis of heart sections revealed that double-mutant mice exhibited complete transposition of the great arteries, an observation not seen in either single mutant. <a href="#17" class="mim-tip-reference" title="Nomi, M., Oishi, I., Kani, S., Suzuki, H., Matsuda, T., Yoda, A., Kitamura, M., Itoh, K., Takeuchi, S., Takeda, K., Akira, S., Ikeya, M., Takada, S., Minami, Y. <strong>Loss of mRor1 enhances the heart and skeletal abnormalities in mRor2-deficient mice: redundant and pleiotropic functions of mRor1 and mRor2 receptor tyrosine kinases.</strong> Molec. Cell. Biol. 21: 8329-8335, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11713269/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11713269</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11713269[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/10.1128/MCB.21.24.8329-8335.2001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11713269">Nomi et al. (2001)</a> concluded that Ror1 and Ror2 are functionally redundant and that they interact genetically in skeletal and cardiac development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11713269" 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="Oishi, I., Suzuki, H., Onishi, N., Takada, R., Kani, S., Ohkawara, B., Koshida, I., Suzuki, K., Yamada, G., Schwabe, G. C., Mundlos, S., Shibuya, H., Takada, S., Minami, Y. <strong>The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway.</strong> Genes Cells 8: 645-654, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12839624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12839624</a>] [<a href="https://doi.org/10.1046/j.1365-2443.2003.00662.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12839624">Oishi et al. (2003)</a> found that both Ror2-null and Wnt5a (<a href="/entry/164975">164975</a>)-null mice showed dwarfism, facial abnormalities, short limbs and tails, dysplasia of lungs and genitals, and ventricular septal defects. In vitro binding assay revealed that Wnt5a binds to the Ror2 and activates the noncanonical Wnt pathway. The findings indicated that Wnt5a and Ror2 interact physically and functionally, and suggested that Ror2 acts as a receptor for Wnt5a to activate noncanonical Wnt signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12839624" 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="#25" class="mim-tip-reference" title="Schwabe, G. C., Trepczik, B., Suring, K., Brieske, N., Tucker, A. S., Sharpe, P. T., Minami, Y., Mundlos, S. <strong>Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome.</strong> Dev. Dyn. 229: 400-410, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14745966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14745966</a>] [<a href="https://doi.org/10.1002/dvdy.10466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14745966">Schwabe et al. (2004)</a> analyzed Ror2 -/- mice as a model for the developmental pathology of Robinow syndrome. They demonstrated that vertebral malformations in the mutant mice were due to reductions in the presomitic mesoderm and defects in somitogenesis. Mesomelic limb shortening in the mice was a consequence of perturbed chondrocyte differentiation. The craniofacial phenotype was caused by a midline outgrowth defect. Ror2 expression in the genital tubercle and its reduced size in Ror2 -/- mice suggested that Ror2 is involved in genital development. <a href="#25" class="mim-tip-reference" title="Schwabe, G. C., Trepczik, B., Suring, K., Brieske, N., Tucker, A. S., Sharpe, P. T., Minami, Y., Mundlos, S. <strong>Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome.</strong> Dev. Dyn. 229: 400-410, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14745966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14745966</a>] [<a href="https://doi.org/10.1002/dvdy.10466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14745966">Schwabe et al. (2004)</a> concluded that ROR2 is essential at multiple sites during development and that the Ror2 -/- mouse provides a suitable model for the study of the underlying developmental malformations in individuals with Robinow syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14745966" 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 an affected member of a family with brachydactyly type B (BDB1; <a href="/entry/113000">113000</a>), <a href="#20" class="mim-tip-reference" title="Oldridge, M., Fortuna, A. M., Maringa, M., Propping, P., Mansour, S., Pollitt, C., DeChiara, T. M., Kimble, R. B., Valenzuela, D. M., Yancopoulos, G. D., Wilkie, A. O. M. <strong>Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.</strong> Nature Genet. 24: 275-278, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10700182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10700182</a>] [<a href="https://doi.org/10.1038/73495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10700182">Oldridge et al. (2000)</a> found heterozygosity for a 2265C-A transversion in the ROR2 gene, resulting in a tyr755-to-ter mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10700182" 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="Hamamy, H., Saleh, N., Oldridge, M., Al-Hadidy, A., Ajlouni, K. <strong>Brachydactyly type B1: report of a family with de novo ROR2 mutation. (Letter)</strong> Clin. Genet. 70: 538-540, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17101003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17101003</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00719.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17101003">Hamamy et al. (2006)</a> reported a Jordanian man with brachydactyly type B who had a heterozygous Y755X mutation. He had a severe form of the disease with classic brachydactyly and specific facial features, including prominent nose, high nasal bridge, hypoplastic alae nasi, and high-arched palate. His 3-year-old affected son also had the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17101003" 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 an affected member of a family with brachydactyly type B (BDB1; <a href="/entry/113000">113000</a>), <a href="#20" class="mim-tip-reference" title="Oldridge, M., Fortuna, A. M., Maringa, M., Propping, P., Mansour, S., Pollitt, C., DeChiara, T. M., Kimble, R. B., Valenzuela, D. M., Yancopoulos, G. D., Wilkie, A. O. M. <strong>Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.</strong> Nature Genet. 24: 275-278, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10700182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10700182</a>] [<a href="https://doi.org/10.1038/73495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10700182">Oldridge et al. (2000)</a> found heterozygosity for a 2246G-A transition in the ROR2 gene, resulting in a trp749-to-ter (W749X) change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10700182" 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>The same W749X substitution was described in a Welsh family, first described by <a href="#22" class="mim-tip-reference" title="Schott, G. D. <strong>Hereditary brachydactyly with nail dysplasia.</strong> J. Med. Genet. 15: 119-122, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/641944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">641944</a>] [<a href="https://doi.org/10.1136/jmg.15.2.119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="641944">Schott (1978)</a> as having a condition he termed hereditary brachydactyly with nail dysplasia, but the base change in that case was a heterozygous 2247G-A transition (<a href="#0009">602337.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=641944" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 BRACHYDACTYLY, TYPE B1</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">rs863223289 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863223289;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=rs863223289" 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=rs863223289" 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 affected member of a family with brachydactyly type B (BDB1; <a href="/entry/113000">113000</a>), <a href="#20" class="mim-tip-reference" title="Oldridge, M., Fortuna, A. M., Maringa, M., Propping, P., Mansour, S., Pollitt, C., DeChiara, T. M., Kimble, R. B., Valenzuela, D. M., Yancopoulos, G. D., Wilkie, A. O. M. <strong>Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.</strong> Nature Genet. 24: 275-278, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10700182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10700182</a>] [<a href="https://doi.org/10.1038/73495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10700182">Oldridge et al. (2000)</a> found a 1-bp deletion, 2249delG, in the ROR2 gene leading to a frameshift at gly750 with an arginine/proline-rich sequence of 23 novel amino acids before the first stop codon. The phenotype also included cutaneous syndactyly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10700182" 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="#13" class="mim-tip-reference" title="Lv, D., Luo, Y., Yang, W., Cao, L., Wen, Y., Zhao, X., Sun, M., Lo, W. H.-Y., Zhang, X. <strong>A novel single-base deletion in ROR2 causes atypical brachydactyly type B1 with cutaneous syndactyly in a large Chinese family.</strong> J. Hum. Genet. 54: 422-425, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19461659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19461659</a>] [<a href="https://doi.org/10.1038/jhg.2009.48" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19461659">Lv et al. (2009)</a> reported a Chinese family with a similar phenotype, including cutaneous syndactyly, with a similar mutation (2243delC; <a href="#0014">602337.0014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19461659" 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> rs121909083 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909083;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/rs121909083?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=rs121909083" 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=rs121909083" 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=RCV000007730" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007730" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007730</a>
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<p>In 14 patients with recessive Robinow syndrome (RRS1; <a href="/entry/268310">268310</a>) from 7 families from Oman, <a href="#2" class="mim-tip-reference" title="Afzal, A. R., Rajab, A., Fenske, C. D., Oldridge, M., Elanko, N., Ternes-Pereira, E., Tuysuz, B., Murday, V. A., Patton, M. A., Wilkie, A. O. M., Jeffery, S. <strong>Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2.</strong> Nature Genet. 25: 419-422, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10932186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10932186</a>] [<a href="https://doi.org/10.1038/78107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10932186">Afzal et al. (2000)</a> identified a gln502-to-ter (Q502X) nonsense mutation in exon 9 of the ROR2 gene that removed the tyrosine kinase domain and all subsequent 3-prime regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10932186" 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> rs121909084 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909084;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/rs121909084?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=rs121909084" 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=rs121909084" 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=RCV000007731 OR RCV005042008" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007731, RCV005042008" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007731...</a>
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<p>In 3 Brazilian sibs with autosomal recessive Robinow syndrome (RRS1; <a href="/entry/268310">268310</a>), <a href="#2" class="mim-tip-reference" title="Afzal, A. R., Rajab, A., Fenske, C. D., Oldridge, M., Elanko, N., Ternes-Pereira, E., Tuysuz, B., Murday, V. A., Patton, M. A., Wilkie, A. O. M., Jeffery, S. <strong>Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2.</strong> Nature Genet. 25: 419-422, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10932186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10932186</a>] [<a href="https://doi.org/10.1038/78107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10932186">Afzal et al. (2000)</a> identified a 550C-T transition in exon 5 of the ROR2 gene, resulting in an arg184-to-cys (R184C) missense change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10932186" 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 40-year-old German man with autosomal recessive Robinow syndrome, <a href="#28" class="mim-tip-reference" title="Tufan, F., Cefle, K., Turkmen, S., Turkmen, A., Zorba, U., Dursun, M., Ozturk, S., Palanduz, S., Ecder, T., Mundlos, S., Horn, D. <strong>Clinical and molecular characterization of two adults with autosomal recessive Robinow syndrome.</strong> Am. J. Med. Genet. 136A: 185-189, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15952209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15952209</a>] [<a href="https://doi.org/10.1002/ajmg.a.30785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15952209">Tufan et al. (2005)</a> identified compound heterozygosity for the R184C mutation and a 355C-T transition in exon 3 of the ROR2 gene, resulting in an arg119-to-ter (R119X; <a href="#0011">602337.0011</a>) substitution in the Ig domain. The nonconsanguineous father and mother were heterozygous for R184C and R119X, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15952209" 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 bioinformatic analysis and immunoprecipitation studies, <a href="#6" class="mim-tip-reference" title="Chen, Y., Bellamy, W. P., Seabra, M. C., Field, M. C., Ali, B. R. <strong>ER-associated protein degradation is a common mechanism underpinning numerous monogenic diseases including Robinow syndrome.</strong> Hum. Molec. Genet. 14: 2559-2569, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16049033/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16049033</a>] [<a href="https://doi.org/10.1093/hmg/ddi259" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16049033">Chen et al. (2005)</a> showed that endoplasmic reticulum (ER) retention was the mechanism underlying RRS1. Specifically, mutant alleles of ROR2, including the R184C mutation, that are associated with RRS1 were retained within the ER, whereas wildtype and nonpathogenic alleles were exported to the plasma membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16049033" 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">rs121909085 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909085;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=rs121909085" 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=rs121909085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a family of Turkish descent with autosomal recessive Robinow syndrome (RRS1; <a href="/entry/268310">268310</a>), <a href="#30" class="mim-tip-reference" title="van Bokhoven, H., Celli, J., Kayserili, H., van Beusekom, E., Balci, S., Brussel, W., Skovby, F., Kerr, B., Percin, E. F., Akarsu, N., Brunner, H. G. <strong>Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome.</strong> Nature Genet. 25: 423-426, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10932187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10932187</a>] [<a href="https://doi.org/10.1038/78113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10932187">van Bokhoven et al. (2000)</a> demonstrated that the ROR2 gene in affected individuals carried a homozygous nonsense mutation, trp720 to ter (W720X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10932187" 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> rs121909086 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909086;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/rs121909086?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=rs121909086" 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=rs121909086" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 consanguineous Turkish families with autosomal recessive Robinow syndrome (RRS1; <a href="/entry/268310">268310</a>), <a href="#30" class="mim-tip-reference" title="van Bokhoven, H., Celli, J., Kayserili, H., van Beusekom, E., Balci, S., Brussel, W., Skovby, F., Kerr, B., Percin, E. F., Akarsu, N., Brunner, H. G. <strong>Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome.</strong> Nature Genet. 25: 423-426, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10932187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10932187</a>] [<a href="https://doi.org/10.1038/78113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10932187">van Bokhoven et al. (2000)</a> demonstrated that affected members carried an arg205-to-ter (R205X) nonsense mutation in the ROR2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10932187" 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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ROBINOW SYNDROME, AUTOSOMAL RECESSIVE, WITH APLASIA/HYPOPLASIA OF PHALANGES AND METACARPALS/METATARSALS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs863223290 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863223290;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=rs863223290" 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=rs863223290" 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=RCV000007734 OR RCV000007735" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007734, RCV000007735" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007734...</a>
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<p>In an extensive Turkish kindred, <a href="#24" class="mim-tip-reference" title="Schwabe, G. C., Tinschert, S., Buschow, C., Meinecke, P., Wolff, G., Gillessen-Kaesbach, G., Oldridge, M., Wilkie, A. O. M., Komec, R., Mundlos, S. <strong>Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.</strong> Am. J. Hum. Genet. 67: 822-831, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10986040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10986040</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10986040[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/10.1086/303084" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10986040">Schwabe et al. (2000)</a> demonstrated that type B brachydactyly (BDB1; <a href="/entry/113000">113000</a>) was caused by a heterozygous 5-bp deletion (1321delCGGCG) in exon 8 of the ROR2 gene, proximal to the tyrosine kinase domain, resulting in a frameshift and a stop codon after 14 amino acids. One individual in this family, born of consanguineous parents who both had BDB1, was homozygous for the 5-bp deletion. He had particularly severe skeletal manifestations and a ventricular septal defect. His phenotype resembled an extreme form of brachydactyly, with extensive aplasia/hypoplasia of the phalanges and metacarpals/metatarsals and absence of nails (see <a href="/entry/268310">268310</a>). Vertebral anomalies, brachymelia of the arms, and a ventricular septal defect were features reminiscent of Robinow syndrome, but he lacked the craniofacial features of Robinow syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10986040" 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">rs104894121 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894121;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=rs104894121" 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=rs104894121" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a Welsh family described by <a href="#22" class="mim-tip-reference" title="Schott, G. D. <strong>Hereditary brachydactyly with nail dysplasia.</strong> J. Med. Genet. 15: 119-122, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/641944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">641944</a>] [<a href="https://doi.org/10.1136/jmg.15.2.119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="641944">Schott (1978)</a> with a disorder he designated hereditary brachydactyly with nail dysplasia (HPND), <a href="#4" class="mim-tip-reference" title="Bacchelli, C., Wilson, L. C., Cook, J. A., Winter, R. M., Goodman, F. R. <strong>ROR2 is mutated in hereditary brachydactyly with nail dysplasia, but not in Sorsby syndrome. (Letter)</strong> Clin. Genet. 64: 263-265, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12919145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12919145</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00139.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12919145">Bacchelli et al. (2003)</a> found a heterozygous G-to-A transition in exon 9 of the ROR2 gene (2247G-A), which converted amino acid 749 from tryptophan to a premature stop. Contrary to the previous report by <a href="#22" class="mim-tip-reference" title="Schott, G. D. <strong>Hereditary brachydactyly with nail dysplasia.</strong> J. Med. Genet. 15: 119-122, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/641944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">641944</a>] [<a href="https://doi.org/10.1136/jmg.15.2.119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="641944">Schott (1978)</a>, who thought the disorder was distinct from brachydactyly type B1 (BDB1; <a href="/entry/113000">113000</a>) due to lack of foot involvement, <a href="#4" class="mim-tip-reference" title="Bacchelli, C., Wilson, L. C., Cook, J. A., Winter, R. M., Goodman, F. R. <strong>ROR2 is mutated in hereditary brachydactyly with nail dysplasia, but not in Sorsby syndrome. (Letter)</strong> Clin. Genet. 64: 263-265, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12919145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12919145</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00139.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12919145">Bacchelli et al. (2003)</a> found subtle foot involvement and a facial appearance typical of BDB. Typical BDB due to a nonsense mutation in the same codon but resulting from a different base change was reported in a German family with typical BDB by <a href="#20" class="mim-tip-reference" title="Oldridge, M., Fortuna, A. M., Maringa, M., Propping, P., Mansour, S., Pollitt, C., DeChiara, T. M., Kimble, R. B., Valenzuela, D. M., Yancopoulos, G. D., Wilkie, A. O. M. <strong>Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.</strong> Nature Genet. 24: 275-278, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10700182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10700182</a>] [<a href="https://doi.org/10.1038/73495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10700182">Oldridge et al. (2000)</a>; see <a href="#0002">602337.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12919145+641944+10700182" 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">rs863223291 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863223291;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=rs863223291" 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=rs863223291" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 28-year-old Turkish man, born of first-cousin parents, who had autosomal recessive Robinow syndrome (RRS1; <a href="/entry/268310">268310</a>), <a href="#28" class="mim-tip-reference" title="Tufan, F., Cefle, K., Turkmen, S., Turkmen, A., Zorba, U., Dursun, M., Ozturk, S., Palanduz, S., Ecder, T., Mundlos, S., Horn, D. <strong>Clinical and molecular characterization of two adults with autosomal recessive Robinow syndrome.</strong> Am. J. Med. Genet. 136A: 185-189, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15952209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15952209</a>] [<a href="https://doi.org/10.1002/ajmg.a.30785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15952209">Tufan et al. (2005)</a> identified homozygosity for a 7-bp deletion (1937delACAAGCT) in exon 9 of the ROR2 gene. His parents were both heterozygous for the deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15952209" 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">rs121909087 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909087;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=rs121909087" 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=rs121909087" 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 arg119-to-ter (R119X) mutation in the ROR2 gene that was found in compound heterozygous state in a patient with autosomal recessive Robinow syndrome (RRS1; <a href="/entry/268310">268310</a>) by <a href="#28" class="mim-tip-reference" title="Tufan, F., Cefle, K., Turkmen, S., Turkmen, A., Zorba, U., Dursun, M., Ozturk, S., Palanduz, S., Ecder, T., Mundlos, S., Horn, D. <strong>Clinical and molecular characterization of two adults with autosomal recessive Robinow syndrome.</strong> Am. J. Med. Genet. 136A: 185-189, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15952209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15952209</a>] [<a href="https://doi.org/10.1002/ajmg.a.30785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15952209">Tufan et al. (2005)</a>, see <a href="#0005">602337.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15952209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007739" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007739" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007739</a>
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<p>In 2 sib pairs with Robinow syndrome (RRS1; <a href="/entry/268310">268310</a>) from the same extended family, <a href="#5" class="mim-tip-reference" title="Brunetti-Pierri, N., del Gaudio, D., Peters, H., Justino, H., Ott, C.-E., Mundlos, S., Bacino, C. A. <strong>Robinow syndrome: phenotypic variability in a family with a novel intragenic ROR2 mutation.</strong> Am. J. Med. Genet. 146A: 2804-2809, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18831060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18831060</a>] [<a href="https://doi.org/10.1002/ajmg.a.32530" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18831060">Brunetti-Pierri et al. (2008)</a> identified homozygosity for an 8,851-bp deletion encompassing exons 6 and 7 of the ROR2 gene, with the centromeric breakpoint between nucleotides 93529881 and 93529882 on chromosome 9 and the telomeric breakpoint between nucleotides 93538732 and 93538733. All 4 unaffected parents were heterozygous for the deletion. The patients demonstrated intrafamilial variability with respect to cleft lip, cleft palate, and cardiac abnormalities. One of the sibs presented at age 17 with back pain, and spine MRI revealed a thoracic syringomyelia, which had not previously been reported in Robinow syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18831060" 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">rs1587657302 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1587657302;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=rs1587657302" 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=rs1587657302" 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=RCV000007740 OR RCV004589500" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007740, RCV004589500" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007740...</a>
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<p>In 10 affected and 3 unaffected members of a large Turkish family with a mild brachydactyly type B1 phenotype (BDB1; <a href="/entry/113000">113000</a>), <a href="#12" class="mim-tip-reference" title="Kjaer, K. W., Tiner, M., Cingoz, S., Karatosun, V., Tommerup, N., Mundlos, S., Gunal, I. <strong>A novel subtype of distal symphalangism affecting only the 4th finger. (Letter)</strong> Am. J. Med. Genet. 149A: 1571-1573, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19533773/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19533773</a>] [<a href="https://doi.org/10.1002/ajmg.a.32905" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19533773">Kjaer et al. (2009)</a> identified a heterozygous 1-bp insertion (1366insC) in exon 9 of the ROR2 gene. The authors stated that this family presented the mildest mutation-positive BDB1 phenotype reported to date, with 3 unaffected ROR2 mutation carriers and only 3 carriers with the typical BDB1 distal reductions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19533773" 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">rs863223292 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863223292;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=rs863223292" 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=rs863223292" 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=RCV000007741" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007741" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007741</a>
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<p>In affected members of a large Chinese family with brachydactyly type 1 and various degrees of cutaneous syndactyly (BDB1; <a href="/entry/113000">113000</a>), <a href="#13" class="mim-tip-reference" title="Lv, D., Luo, Y., Yang, W., Cao, L., Wen, Y., Zhao, X., Sun, M., Lo, W. H.-Y., Zhang, X. <strong>A novel single-base deletion in ROR2 causes atypical brachydactyly type B1 with cutaneous syndactyly in a large Chinese family.</strong> J. Hum. Genet. 54: 422-425, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19461659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19461659</a>] [<a href="https://doi.org/10.1038/jhg.2009.48" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19461659">Lv et al. (2009)</a> identified a heterozygous 1-bp deletion (2243delC) in exon 9 of the ROR2 gene, predicted to result in a truncated protein with an additional C-terminal polypeptide of 24 residues. <a href="#13" class="mim-tip-reference" title="Lv, D., Luo, Y., Yang, W., Cao, L., Wen, Y., Zhao, X., Sun, M., Lo, W. H.-Y., Zhang, X. <strong>A novel single-base deletion in ROR2 causes atypical brachydactyly type B1 with cutaneous syndactyly in a large Chinese family.</strong> J. Hum. Genet. 54: 422-425, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19461659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19461659</a>] [<a href="https://doi.org/10.1038/jhg.2009.48" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19461659">Lv et al. (2009)</a> noted that a Portuguese family with a similar phenotype including cutaneous syndactyly had a similar mutation (2249delG; <a href="#0003">602337.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19461659" 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>.0015 ROBINOW SYNDROME, AUTOSOMAL RECESSIVE, WITH BRACHY-SYN-POLYDACTYLY</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> rs267607016 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607016;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/rs267607016?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=rs267607016" 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=rs267607016" 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=RCV000007742 OR RCV000761457 OR RCV003441709 OR RCV005042009" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007742, RCV000761457, RCV003441709, RCV005042009" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007742...</a>
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<p><a href="#26" class="mim-tip-reference" title="Schwarzer, W., Witte, F., Rajab, A., Mundlos, S., Stricker, S. <strong>A gradient of ROR2 protein stability and membrane localization confers brachydactyly type B or Robinow syndrome phenotypes.</strong> Hum. Molec. Genet. 18: 4013-4021, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19640924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19640924</a>] [<a href="https://doi.org/10.1093/hmg/ddp345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19640924">Schwarzer et al. (2009)</a> identified homozygosity for a 1324C-T transition in the ROR2 gene, resulting in an arg441-to-ter (R441X) substitution, in a 9-month old Omani child exhibiting features of Robinow syndrome in conjunction with complex, symmetric brachy-syn-polydactyly of the hands and oligodactyly of the feet with absent toes 2 to 4 (see <a href="/entry/268310">268310</a>). The Omani parents were healthy, had no features of Robinow syndrome or brachydactyly type B1 (<a href="/entry/113000">113000</a>), and were distantly related by mothers of the same tribal background. The mutation was located at the same position as a frameshift mutation (<a href="#0008">602337.0008</a>) causing dominant BDB1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19640924" 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>One gene, two phenotypes: ROR2 mutations in autosomal recessive Robinow syndrome and autosomal dominant brachydactyly type B.</strong>
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Hum. Mutat. 22: 1-11, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12815588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12815588</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12815588" 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.10233" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/78107" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-007-0409-0" target="_blank">Full Text</a>]
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<strong>ROR2 is mutated in hereditary brachydactyly with nail dysplasia, but not in Sorsby syndrome. (Letter)</strong>
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[<a href="https://doi.org/10.1034/j.1399-0004.2003.00139.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32530" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi259" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.282.5389.744" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/302249" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32905" target="_blank">Full Text</a>]
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Oishi, I., Suzuki, H., Onishi, N., Takada, R., Kani, S., Ohkawara, B., Koshida, I., Suzuki, K., Yamada, G., Schwabe, G. C., Mundlos, S., Shibuya, H., Takada, S., Minami, Y.
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<strong>The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12839624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12839624</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12839624" 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/10.1046/j.1365-2443.2003.00662.x" target="_blank">Full Text</a>]
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Oishi, I., Takeuchi, S., Hashimoto, R., Nagabukuro, A., Ueda, T., Liu, Z.-J., Hatta, T., Akira, S., Matsuda, Y., Yamamura, H., Otani, H., Minami, Y.
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<strong>Spatio-temporally regulated expression of receptor tyrosine kinases, mRor1, mRor2, during mouse development: implications in development and function of the nervous system.</strong>
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[<a href="https://doi.org/10.1046/j.1365-2443.1999.00234.x" target="_blank">Full Text</a>]
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Oldridge, M., Fortuna, A. M., Maringa, M., Propping, P., Mansour, S., Pollitt, C., DeChiara, T. M., Kimble, R. B., Valenzuela, D. M., Yancopoulos, G. D., Wilkie, A. O. M.
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<strong>Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.</strong>
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[<a href="https://doi.org/10.1038/73495" target="_blank">Full Text</a>]
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<a id="Oldridge1999" class="mim-anchor"></a>
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<div class="">
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9973296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9973296</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9973296" 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/10.1086/302255" target="_blank">Full Text</a>]
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<a id="Schott1978" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/641944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">641944</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=641944" 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.15.2.119" target="_blank">Full Text</a>]
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<a id="Schott1979" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/469906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">469906</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=469906" 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.16.3.236" target="_blank">Full Text</a>]
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Schwabe, G. C., Tinschert, S., Buschow, C., Meinecke, P., Wolff, G., Gillessen-Kaesbach, G., Oldridge, M., Wilkie, A. O. M., Komec, R., Mundlos, S.
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<strong>Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.</strong>
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Am. J. Hum. Genet. 67: 822-831, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10986040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10986040</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10986040[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=10986040" 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/10.1086/303084" target="_blank">Full Text</a>]
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Schwabe, G. C., Trepczik, B., Suring, K., Brieske, N., Tucker, A. S., Sharpe, P. T., Minami, Y., Mundlos, S.
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<strong>Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14745966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14745966</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14745966" 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/dvdy.10466" target="_blank">Full Text</a>]
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<a id="Schwarzer2009" class="mim-anchor"></a>
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Schwarzer, W., Witte, F., Rajab, A., Mundlos, S., Stricker, S.
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<strong>A gradient of ROR2 protein stability and membrane localization confers brachydactyly type B or Robinow syndrome phenotypes.</strong>
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Hum. Molec. Genet. 18: 4013-4021, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19640924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19640924</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19640924" 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/ddp345" target="_blank">Full Text</a>]
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Takeuchi, S., Takeda, K., Oishi, I., Nomi, M., Ikeya, M., Itoh, K., Tamura, S., Ueda, T., Hatta, T., Otani, H., Terashima, T., Takada, S., Yamamura, H., Akira, S., Minami, Y.
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<strong>Mouse Ror2 receptor tyrosine kinase is required for the heart development and limb formation.</strong>
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Genes Cells 5: 71-78, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10651906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10651906</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10651906" 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/10.1046/j.1365-2443.2000.00300.x" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15952209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15952209</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15952209" 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.a.30785" target="_blank">Full Text</a>]
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van Bokhoven, H., Brunner, H. G.
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<strong>Splitting p63.</strong>
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Am. J. Hum. Genet. 71: 1-13, 2002. Note: Erratum: Am. J. Hum. Genet. 72: 779 only, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12037717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12037717</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12037717[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=12037717" 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/10.1086/341450" target="_blank">Full Text</a>]
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van Bokhoven, H., Celli, J., Kayserili, H., van Beusekom, E., Balci, S., Brussel, W., Skovby, F., Kerr, B., Percin, E. F., Akarsu, N., Brunner, H. G.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10932187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10932187</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10932187" 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/10.1038/78113" target="_blank">Full Text</a>]
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Zhang, C., Brunt, L., Ono, Y., Rogers, S., Scholpp, S.
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<strong>Cytoneme-mediated transport of active Wnt5b-Ror2 complexes in zebrafish.</strong>
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Nature 625: 126-133, 2024.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38123680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38123680</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38123680[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=38123680" 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/s41586-023-06850-7" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<span class="mim-text-font">
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Bao Lige - updated : 03/04/2024
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 8/15/2011<br>George E. Tiller - updated : 9/30/2010<br>Cassandra L. Kniffin - updated : 1/7/2010<br>Marla J. F. O'Neill - updated : 12/4/2009<br>Marla J. F. O'Neill - updated : 8/31/2009<br>George E. Tiller - updated : 1/23/2009<br>Marla J. F. O'Neill - updated : 5/29/2008<br>Cassandra L. Kniffin - updated : 5/7/2007<br>Marla J. F. O'Neill - updated : 12/28/2005<br>Gregory S. Antonarakis - updated : 9/26/2005<br>Victor A. McKusick - updated : 10/16/2003<br>Victor A. McKusick - updated : 8/21/2003<br>Victor A. McKusick - updated : 7/17/2002<br>Dawn Watkins-Chow - updated : 4/17/2002<br>Victor A. McKusick - updated : 10/20/2000<br>Victor A. McKusick - updated : 7/31/2000<br>Victor A. McKusick - updated : 3/1/2000
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Rebekah S. Rasooly : 2/10/1998
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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mgross : 03/04/2024
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carol : 08/09/2019<br>alopez : 08/08/2019<br>carol : 09/18/2015<br>mcolton : 8/18/2015<br>carol : 4/3/2015<br>carol : 5/2/2013<br>alopez : 8/19/2011<br>ckniffin : 8/15/2011<br>wwang : 10/12/2010<br>terry : 9/30/2010<br>wwang : 1/22/2010<br>ckniffin : 1/7/2010<br>carol : 12/23/2009<br>terry : 12/4/2009<br>carol : 9/2/2009<br>terry : 8/31/2009<br>wwang : 1/23/2009<br>carol : 5/30/2008<br>terry : 5/29/2008<br>wwang : 5/29/2007<br>ckniffin : 5/7/2007<br>wwang : 12/29/2005<br>terry : 12/28/2005<br>carol : 9/26/2005<br>carol : 6/2/2005<br>carol : 3/10/2005<br>cwells : 10/21/2003<br>terry : 10/16/2003<br>cwells : 8/21/2003<br>carol : 8/18/2003<br>tkritzer : 7/26/2002<br>terry : 7/17/2002<br>mgross : 4/17/2002<br>mcapotos : 4/10/2001<br>carol : 3/2/2001<br>mcapotos : 11/6/2000<br>mcapotos : 10/30/2000<br>terry : 10/20/2000<br>alopez : 10/11/2000<br>alopez : 7/31/2000<br>terry : 7/31/2000<br>terry : 7/31/2000<br>alopez : 3/1/2000<br>terry : 3/1/2000<br>mgross : 2/28/2000<br>alopez : 2/10/1998
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<strong>*</strong> 602337
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RECEPTOR TYROSINE KINASE-LIKE ORPHAN RECEPTOR 2; ROR2
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<em>Alternative titles; symbols</em>
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NEUROTROPHIC TYROSINE KINASE, RECEPTOR-RELATED 2; NTRKR2
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ROR2</em></strong>
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Cytogenetic location: 9q22.31
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Genomic coordinates <span class="small">(GRCh38)</span> : 9:91,722,601-91,950,228 </span>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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9q22.31
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Brachydactyly, type B1
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<span class="mim-font">
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113000
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Autosomal dominant
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3
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Robinow syndrome, autosomal recessive
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268310
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Autosomal recessive
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The receptor tyrosine kinases (RTK), including ROR1, are a large superfamily of transmembrane glycoproteins that function as cell surface receptors. RTKs play a role in the control of most basic cellular processes including cell proliferation, differentiation, migration and metabolism (summary by Afzal and Jeffery, 2003). </p>
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<strong>Cloning and Expression</strong>
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<p>By degenerate PCR using primers based on conserved regions of NTRK1 (191315) and NTRK2 (600456), Masiakowski and Carroll (1992) identified 2 additional members of the TRK family, NTRKR1 (ROR1; 602336) and NTRKR2, also called ROR2. Masiakowski and Carroll (1992) showed that NTRKR2 encodes a predicted 943-amino acid protein with in vitro protein kinase activity. </p><p>Receptor tyrosine kinases often have critical roles in particular cell lineages by initiating signal cascades in those lineages. Many lineage-restricted receptor tyrosine kinases were initially identified as 'orphans' homologous to known receptors, and only subsequently used to identify their unknown growth factors. DeChiara et al. (2000) identified one such orphan, encoded by Ror2. They reported that disruption of mouse Ror2 leads to profound skeletal abnormalities, with essentially all endochondrally derived bones foreshortened or misshapen, albeit to differing degrees. Further, they found that Ror2 is selectively expressed in the chondrocytes of all developing cartilage anlagen, where it is essential during initial growth and patterning, as well as subsequently in the proliferating chondrocytes of mature growth plates, where it is required for normal expansion. Thus, Ror2 encodes a receptor-like tyrosine kinase that is selectively expressed in, and particularly important for, the chondrocyte lineage. </p>
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<strong>Mapping</strong>
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<p>By radiation hybrid mapping between D9S1842 and D9S196 on 2 independent panels, Deloukas et al., 1998 mapped the ROR2 gene to chromosome 9q22. By FISH analysis, Oldridge et al., 2000 confirmed localization of the ROR2 gene to chromosome 9q22. </p><p>The mouse Ror2 gene maps to chromosome 13, in a region of conserved synteny with human chromosome 9q (Oishi et al., 1999). </p>
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<strong>Gene Function</strong>
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<p>Using mouse proteins, Mikels and Nusse (2006) demonstrated that Ror2 is a receptor for Wnt5a (164975) and serves to inhibit canonical Wnt signaling. </p><p>By immunostaining, Zhang et al. (2024) showed that ligand wnt5b (606361) and its plasma membrane-bound receptor ror2 were expressed and colocalized on cell protrusions in PAC2 zebrafish fibroblasts. Overexpression and knockout analyses in PAC2 cells revealed that wnt5b and ror2 formed a ligand-receptor complex and were transported from producing cells to receiving cells. During transport, wnt5b and the N-terminal part of ror2 faced the extracellular side of the membrane and were loaded together on signaling filopodia that the authors referred to as cytonemes, and the ligand-receptor complex was taken up by dynamin-dependent endocytosis into receiving cells via the cytonemes. The same transport was seen in zebrafish embryos, and further analysis with living zebrafish embryos indicated that ror2 bound to wnt5b with high affinity at the plasma membrane of producing cells, and that structural integrity of the complex was maintained during both transportation and subsequent uptake into receiving cells. Knockout and overexpression analyses in zebrafish revealed that wnt5b-ror2 regulated cytoneme formation, as binding between wnt5b and ror2 triggered the Wnt-planar cell polarity (PCP) signaling pathway, which induced long wnt5b-ror2-bearing cytonemes to facilitate spreading of wnt5b and ror2. The cytonemes were stabilized through irsp53 (BAIAP2; 605475) and Wnt-JNK (see 601158) signaling, and ror2 directly delivered by cytonemes was required for paracrine Wnt-JNK activation, indicating that the transferred wnt5b-ror2 complex maintained its activity in target cells. In addition to activating JNK signaling, paracrine ror2 also repressed beta-catenin (CTNNB1; 116806) signaling, thereby influencing convergence and extension in zebrafish development. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p><strong><em>Brachydactyly, Type B1</em></strong></p><p>
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Inherited limb malformations provide a valuable resource for identification of genes involved in limb development (Innis and Mortlock, 1998; Manouvrier-Hanu et al., 1999). Brachydactyly type B (BDB1; 113000), an autosomal dominant disorder, is the most severe of the brachydactylies and is characterized by terminal deficiency of the fingers and toes. In the typical form of BDB, the thumbs and big toes are spared, sometimes with broadening or partial duplication. The BDB1 locus was mapped to 9q22 within an interval of 7.5 cM (Gong et al., 1999; Oldridge et al., 1999). Oldridge et al. (2000) identified distinct heterozygous mutations (2 nonsense, 1 frameshift) within a 7-amino acid segment of the 943-amino acid ROR2 protein, all of which predicted truncation of the intracellular portion of the protein immediately after the tyrosine kinase domain. The localized nature of these mutations suggested that they confer a specific gain of function. Oldridge et al. (2000) obtained further evidence for this by demonstrating that 2 patients heterozygous for 9q22 deletions including ROR2 did not exhibit BDB. Expression of the mouse ortholog, Ror2, early in limb development indicated that BDB arises as a primary defect of skeletal patterning. </p><p>In 5 families with BDB, Schwabe et al. (2000) found 4 novel mutations in ROR2: 2 frameshifts (see, e.g., 602337.0008), 1 splice mutation, and 1 nonsense mutation. The mutations predicted truncation of the protein within 2 distinct regions immediately before and after the tyrosine kinase (TK) domain, resulting in a complete or partial loss of the intracellular portion of the protein. Patients with the distal mutations had a more severe phenotype than did those with the proximal mutations. </p><p>Bacchelli et al. (2003) reviewed 4 affected members of a large Welsh family with a dominantly inherited form of isolated brachydactyly first described by Schott (1978), who designated it hereditary brachydactyly with nail dysplasia. Although Schott (1979) recognized that the external and radiologic appearance of the affected individuals' hands were very similar to brachydactyly type B1, he maintained that the disorder could be distinguished from BDB1 by the complete absence of foot involvement. Bacchelli et al. (2003) found, however, that in addition to hand anomalies typical of BDB, affected members of the Welsh kindred had subtle but definite foot involvement, including mild shortening of the second to fifth toes, occasional nail hypoplasia, and clinically evident distal symphalangism. Facial appearance was also typical of BDB, including a short philtrum and a prominent nose with a high bridge and bulbous tip. Direct sequencing of ROR2 demonstrated a nonsense mutation (W749X; 602337.0009). A heterozygous G-to-A transition in exon 9 (2247G-A) was responsible for the premature stop. The same nonsense change in codon 749 had been reported in a German family with typical BDB, although the underlying base change in that family was different (2246G-A). </p><p>In a large Turkish family with a mild BDB1 phenotype, known to be negative for mutation in the NOG (602991) and GDF5 (601146) genes, Kjaer et al. (2009) identified a heterozygous truncating mutation in the ROR2 gene (602337.0013). </p><p><strong><em>Robinow Syndrome, Autosomal Recessive 1</em></strong></p><p>
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autosomal recessive Robinow syndrome-1 (RRS1; 268310) is a severe skeletal dysplasia with generalized shortening of the bones of the limbs, segmental defects of the spine, brachydactyly, and a dysmorphic facial appearance. Afzal et al. (2000) mapped the gene mutant in this disorder to 9q22, a region that overlaps the locus for autosomal dominant brachydactyly type B. The identification of ROR2, encoding a receptor tyrosine kinase, as the gene mutated in brachydactyly type B and in the mesomelic dwarfing in mice homozygous for insertions in the Ror2 gene, made this gene a candidate for autosomal recessive Robinow syndrome. Afzal et al. (2000) reported homozygous missense mutations (e.g., 602337.0005) in both intracellular and extracellular domains of ROR2 in affected individuals from 3 unrelated consanguineous families, and a Q502X mutation (602337.0004) that removed the tyrosine kinase domain in all subsequent 3-prime regions of the gene in 14 patients from 7 families from Oman. The nature of these mutations suggested that this form of Robinow syndrome is caused by loss of ROR2 activity. Identification of mutations from 3 distinct domains (containing frizzled-like, kringle, and tyrosine kinase motifs) indicated that these are all essential for ROR2 function. </p><p>Van Bokhoven et al. (2000) also mapped autosomal recessive Robinow syndrome to chromosome 9q21-q22 and detected homozygous ROR2 mutations in a cohort of 10 families of Turkish descent and 1 of Pakistani descent. </p><p>Tufan et al. (2005) reported 2 patients with autosomal recessive Robinow syndrome and mutations in the ROR2 gene: one homozygous for a deletion (602337.0010) and the other compound heterozygous for a missense (R184C; 602337.0005) and a nonsense (R119X; 602337.0011) mutation. </p><p>By bioinformatic analysis and immunoprecipitation studies, Chen et al. (2005) showed that endoplasmic reticulum (ER) retention was the mechanism underlying Robinow syndrome-1. Specifically, mutant alleles of ROR2, including the R184C mutation, that are associated with autosomal recessive Robinow syndrome were retained within the ER, whereas wildtype and nonpathogenic alleles were exported to the plasma membrane. </p><p>In an unrelated boy and girl with autosomal recessive Robinow syndrome, Ali et al. (2007) identified homozygosity for different missense mutations, respectively, located in the proximal region of the extracellular frizzled-like domain of the ROR2 gene. In studies in HeLa cells, the authors demonstrated that the mutated proteins were retained in the ER and failed to reach the plasma membrane. Noting the clustering of Robinow-causing mutations in the extracellular frizzled-like cysteine-rich domain of ROR2, Ali et al. (2007) suggested that there is a stringent requirement for the correct folding of this domain prior to export of ROR2 from the ER. </p><p>In 2 sib pairs with Robinow syndrome from the same extended family, Brunetti-Pierri et al. (2008) identified homozygosity for a deletion encompassing exons 6 and 7 of the ROR2 gene (602337.0012); all 4 unaffected parents were heterozygous for the deletion. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Van Bokhoven and Brunner (2002) pointed out that the mechanism of divergent phenotypes of disorders caused by allelic mutations is illustrated by dominant BDB and recessive Robinow syndrome which are caused, respectively, by gain-of-function and loss-of-function mutations in the ROR2 gene. </p><p>Afzal and Jeffery (2003) presented a compilation of the defects in the ROR2 gene leading to autosomal recessive Robinow syndrome and autosomal dominant BDB and discussed possible genotype-phenotype correlations. </p><p><strong><em>Recessive Robinow Syndrome with Severe Malformations of the Hands and Feet</em></strong></p><p>
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In a large Turkish kindred in which many members over at least 6 generations had dominant BDB1, Schwabe et al. (2000) described a man, born of consanguineous parents with BDB1, who was homozygous for a 5-bp deletion proximal to the TK domain, resulting in frameshift at the arg441 residue (602337.0008). His phenotype resembled an extreme form of brachydactyly, with extensive aplasia/hypoplasia of the phalanges and metacarpals/metatarsals and absence of nails. In addition, he had vertebral anomalies, brachymelia anomalies (short arms), and a ventricular septal defect--features reminiscent of Robinow syndrome. The phenotype in this patient suggested a specific mutation effect that cannot be explained by simple haploinsufficiency and that is distinct from that in Robinow syndrome. </p><p>Schwarzer et al. (2009) reported an R441X mutation in the ROR2 gene (602337.0014) in an Omani patient exhibiting features of Robinow syndrome in conjunction with complex, symmetric brachy-syn-polydactyly of the hands and oligodactyly of the feet with absent toes 2 to 4. The Omani parents were healthy, had no features of Robinow syndrome or BDB1, and were distantly related by mothers of the same tribal background. The R441X mutation was located at the same position as the frameshift mutation at arg441. Transfection experiments with a series of mutant transcripts revealed that recessive Robinow syndrome (RRS) mutant proteins, such as Q502X and W720X (602337.0006), were less abundant and retained intracellularly, whereas BDB1 mutants, such as W749X, were stable and predominantly located at the cell membrane. Both the frameshift mutation and the R441X mutation showed an intermediate pattern with membrane localization but also high ER retention, although the R441X mutant had a significantly lower total protein level and less membrane-associated protein than the frameshift mutant. There was a correlation between the severity of BDB1, the location of the mutation, and the amount of membrane-associated ROR2. Membrane protein fraction quantification revealed a gradient of distribution and stability correlating with the clinical phenotypes. This gradual model was confirmed by crossing mouse models for RRS and BDB1, yielding double heterozygous animals that exhibited an intermediate phenotype. Schwarzer et al. (2009) proposed a model in which the phenotypic outcome of ROR2 mutations is determined by 2 threshold levels: the degree of protein retention/degradation determines the RRS phenotype, whereas the amount of mutant protein reaching the plasma membrane determines the severity of the BDB1 phenotype. A mixture of both effects can result in a balance of gain of function and loss of function and, consequently, an overlapping phenotype. </p>
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<strong>Animal Model</strong>
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<p>Takeuchi et al. (2000) generated mice with a mutation in the Ror2 gene and observed that homozygous mutant mice died just after birth, exhibiting dwarfism, severe cyanosis, and short limbs and tails. Whole-mount in situ hybridization analysis showed that Ror2 is expressed in the branchial arches, heart, and limb/tailbuds, in addition to the developing nervous system. The Ror2-deficient mice had cardiac septal defects and skeletal abnormalities, including shorter limbs, vertebrae, and facial structure, with a particular defect in their distal portions. Takeuchi et al. (2000) concluded that Ror2 plays essential roles in the development of the heart and in limb/tail formation, in particular cardiac septal formation and ossification of distal portions of limbs and tails. </p><p>Nomi et al. (2001) bred double-mutant mice lacking both the Ror1 and Ror2 genes. Using skeletal preparations, they observed that Ror1/Ror2 double-mutant mice showed skeletal abnormalities more severe than those seen in Ror2 mutant mice, including a sternal defect, dysplasia of the symphysis of the pubic bone. Histologic analysis of heart sections revealed that double-mutant mice exhibited complete transposition of the great arteries, an observation not seen in either single mutant. Nomi et al. (2001) concluded that Ror1 and Ror2 are functionally redundant and that they interact genetically in skeletal and cardiac development. </p><p>Oishi et al. (2003) found that both Ror2-null and Wnt5a (164975)-null mice showed dwarfism, facial abnormalities, short limbs and tails, dysplasia of lungs and genitals, and ventricular septal defects. In vitro binding assay revealed that Wnt5a binds to the Ror2 and activates the noncanonical Wnt pathway. The findings indicated that Wnt5a and Ror2 interact physically and functionally, and suggested that Ror2 acts as a receptor for Wnt5a to activate noncanonical Wnt signaling. </p><p>Schwabe et al. (2004) analyzed Ror2 -/- mice as a model for the developmental pathology of Robinow syndrome. They demonstrated that vertebral malformations in the mutant mice were due to reductions in the presomitic mesoderm and defects in somitogenesis. Mesomelic limb shortening in the mice was a consequence of perturbed chondrocyte differentiation. The craniofacial phenotype was caused by a midline outgrowth defect. Ror2 expression in the genital tubercle and its reduced size in Ror2 -/- mice suggested that Ror2 is involved in genital development. Schwabe et al. (2004) concluded that ROR2 is essential at multiple sites during development and that the Ror2 -/- mouse provides a suitable model for the study of the underlying developmental malformations in individuals with Robinow syndrome. </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>15 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 BRACHYDACTYLY, TYPE B1</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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ROR2, TYR755TER
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<br />
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SNP: rs121909082,
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gnomAD: rs121909082,
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ClinVar: RCV000007727, RCV002468964
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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 affected member of a family with brachydactyly type B (BDB1; 113000), Oldridge et al. (2000) found heterozygosity for a 2265C-A transversion in the ROR2 gene, resulting in a tyr755-to-ter mutation. </p><p>Hamamy et al. (2006) reported a Jordanian man with brachydactyly type B who had a heterozygous Y755X mutation. He had a severe form of the disease with classic brachydactyly and specific facial features, including prominent nose, high nasal bridge, hypoplastic alae nasi, and high-arched palate. His 3-year-old affected son also had the 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>
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<span class="mim-font">
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<strong>.0002 BRACHYDACTYLY, TYPE B1</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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ROR2, TRP749TER
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<br />
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SNP: rs104894121, rs104894122,
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ClinVar: RCV000007728
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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 affected member of a family with brachydactyly type B (BDB1; 113000), Oldridge et al. (2000) found heterozygosity for a 2246G-A transition in the ROR2 gene, resulting in a trp749-to-ter (W749X) change. </p><p>The same W749X substitution was described in a Welsh family, first described by Schott (1978) as having a condition he termed hereditary brachydactyly with nail dysplasia, but the base change in that case was a heterozygous 2247G-A transition (602337.0009). </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>.0003 BRACHYDACTYLY, TYPE B1</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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ROR2, 1-BP DEL, 2249G
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<br />
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SNP: rs863223289,
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ClinVar: RCV000007729
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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 affected member of a family with brachydactyly type B (BDB1; 113000), Oldridge et al. (2000) found a 1-bp deletion, 2249delG, in the ROR2 gene leading to a frameshift at gly750 with an arginine/proline-rich sequence of 23 novel amino acids before the first stop codon. The phenotype also included cutaneous syndactyly. </p><p>Lv et al. (2009) reported a Chinese family with a similar phenotype, including cutaneous syndactyly, with a similar mutation (2243delC; 602337.0014). </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>.0004 ROBINOW SYNDROME, AUTOSOMAL RECESSIVE 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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ROR2, GLN502TER
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<br />
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SNP: rs121909083,
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gnomAD: rs121909083,
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ClinVar: RCV000007730
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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 14 patients with recessive Robinow syndrome (RRS1; 268310) from 7 families from Oman, Afzal et al. (2000) identified a gln502-to-ter (Q502X) nonsense mutation in exon 9 of the ROR2 gene that removed the tyrosine kinase domain and all subsequent 3-prime regions. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 ROBINOW SYNDROME, AUTOSOMAL RECESSIVE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
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ROR2, ARG184CYS
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<br />
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|
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SNP: rs121909084,
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|
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gnomAD: rs121909084,
|
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|
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ClinVar: RCV000007731, RCV005042008
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|
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|
|
</span>
|
|
</div>
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 Brazilian sibs with autosomal recessive Robinow syndrome (RRS1; 268310), Afzal et al. (2000) identified a 550C-T transition in exon 5 of the ROR2 gene, resulting in an arg184-to-cys (R184C) missense change. </p><p>In a 40-year-old German man with autosomal recessive Robinow syndrome, Tufan et al. (2005) identified compound heterozygosity for the R184C mutation and a 355C-T transition in exon 3 of the ROR2 gene, resulting in an arg119-to-ter (R119X; 602337.0011) substitution in the Ig domain. The nonconsanguineous father and mother were heterozygous for R184C and R119X, respectively. </p><p>By bioinformatic analysis and immunoprecipitation studies, Chen et al. (2005) showed that endoplasmic reticulum (ER) retention was the mechanism underlying RRS1. Specifically, mutant alleles of ROR2, including the R184C mutation, that are associated with RRS1 were retained within the ER, whereas wildtype and nonpathogenic alleles were exported to the plasma membrane. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 ROBINOW SYNDROME, AUTOSOMAL RECESSIVE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ROR2, TRP720TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909085,
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|
|
|
|
|
|
|
ClinVar: RCV000007732
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family of Turkish descent with autosomal recessive Robinow syndrome (RRS1; 268310), van Bokhoven et al. (2000) demonstrated that the ROR2 gene in affected individuals carried a homozygous nonsense mutation, trp720 to ter (W720X). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 ROBINOW SYNDROME, AUTOSOMAL RECESSIVE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ROR2, ARG205TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909086,
|
|
|
|
|
|
gnomAD: rs121909086,
|
|
|
|
|
|
ClinVar: RCV000007733
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 consanguineous Turkish families with autosomal recessive Robinow syndrome (RRS1; 268310), van Bokhoven et al. (2000) demonstrated that affected members carried an arg205-to-ter (R205X) nonsense mutation in the ROR2 gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 BRACHYDACTYLY, TYPE B1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
ROBINOW SYNDROME, AUTOSOMAL RECESSIVE, WITH APLASIA/HYPOPLASIA OF PHALANGES AND METACARPALS/METATARSALS
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ROR2, 5-BP DEL, 1321CGGCG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs863223290,
|
|
|
|
|
|
|
|
ClinVar: RCV000007734, RCV000007735
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an extensive Turkish kindred, Schwabe et al. (2000) demonstrated that type B brachydactyly (BDB1; 113000) was caused by a heterozygous 5-bp deletion (1321delCGGCG) in exon 8 of the ROR2 gene, proximal to the tyrosine kinase domain, resulting in a frameshift and a stop codon after 14 amino acids. One individual in this family, born of consanguineous parents who both had BDB1, was homozygous for the 5-bp deletion. He had particularly severe skeletal manifestations and a ventricular septal defect. His phenotype resembled an extreme form of brachydactyly, with extensive aplasia/hypoplasia of the phalanges and metacarpals/metatarsals and absence of nails (see 268310). Vertebral anomalies, brachymelia of the arms, and a ventricular septal defect were features reminiscent of Robinow syndrome, but he lacked the craniofacial features of Robinow syndrome. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 BRACHYDACTYLY, TYPE B1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ROR2, 2247G-A, TRP749TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894121,
|
|
|
|
|
|
|
|
ClinVar: RCV000007736
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Welsh family described by Schott (1978) with a disorder he designated hereditary brachydactyly with nail dysplasia (HPND), Bacchelli et al. (2003) found a heterozygous G-to-A transition in exon 9 of the ROR2 gene (2247G-A), which converted amino acid 749 from tryptophan to a premature stop. Contrary to the previous report by Schott (1978), who thought the disorder was distinct from brachydactyly type B1 (BDB1; 113000) due to lack of foot involvement, Bacchelli et al. (2003) found subtle foot involvement and a facial appearance typical of BDB. Typical BDB due to a nonsense mutation in the same codon but resulting from a different base change was reported in a German family with typical BDB by Oldridge et al. (2000); see 602337.0002. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 ROBINOW SYNDROME, AUTOSOMAL RECESSIVE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
ROR2, 7-BP DEL, NT1937
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs863223291,
|
|
|
|
|
|
|
|
ClinVar: RCV000007737
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 28-year-old Turkish man, born of first-cousin parents, who had autosomal recessive Robinow syndrome (RRS1; 268310), Tufan et al. (2005) identified homozygosity for a 7-bp deletion (1937delACAAGCT) in exon 9 of the ROR2 gene. His parents were both heterozygous for the deletion. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 ROBINOW SYNDROME, AUTOSOMAL RECESSIVE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ROR2, ARG119TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909087,
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|
|
|
|
|
|
|
ClinVar: RCV000007738, RCV000238984
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the arg119-to-ter (R119X) mutation in the ROR2 gene that was found in compound heterozygous state in a patient with autosomal recessive Robinow syndrome (RRS1; 268310) by Tufan et al. (2005), see 602337.0005. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 ROBINOW SYNDROME, AUTOSOMAL RECESSIVE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
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|
ROR2, EX6,7DEL
|
|
|
|
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|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000007739
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sib pairs with Robinow syndrome (RRS1; 268310) from the same extended family, Brunetti-Pierri et al. (2008) identified homozygosity for an 8,851-bp deletion encompassing exons 6 and 7 of the ROR2 gene, with the centromeric breakpoint between nucleotides 93529881 and 93529882 on chromosome 9 and the telomeric breakpoint between nucleotides 93538732 and 93538733. All 4 unaffected parents were heterozygous for the deletion. The patients demonstrated intrafamilial variability with respect to cleft lip, cleft palate, and cardiac abnormalities. One of the sibs presented at age 17 with back pain, and spine MRI revealed a thoracic syringomyelia, which had not previously been reported in Robinow syndrome. </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>.0013 BRACHYDACTYLY, TYPE B1</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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ROR2, 1-BP INS, 1366C
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<br />
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SNP: rs1587657302,
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ClinVar: RCV000007740, RCV004589500
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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 10 affected and 3 unaffected members of a large Turkish family with a mild brachydactyly type B1 phenotype (BDB1; 113000), Kjaer et al. (2009) identified a heterozygous 1-bp insertion (1366insC) in exon 9 of the ROR2 gene. The authors stated that this family presented the mildest mutation-positive BDB1 phenotype reported to date, with 3 unaffected ROR2 mutation carriers and only 3 carriers with the typical BDB1 distal reductions. </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>.0014 BRACHYDACTYLY, TYPE B1</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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ROR2, 1-BP DEL, 2243C
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<br />
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SNP: rs863223292,
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ClinVar: RCV000007741
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a large Chinese family with brachydactyly type 1 and various degrees of cutaneous syndactyly (BDB1; 113000), Lv et al. (2009) identified a heterozygous 1-bp deletion (2243delC) in exon 9 of the ROR2 gene, predicted to result in a truncated protein with an additional C-terminal polypeptide of 24 residues. Lv et al. (2009) noted that a Portuguese family with a similar phenotype including cutaneous syndactyly had a similar mutation (2249delG; 602337.0003). </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>.0015 ROBINOW SYNDROME, AUTOSOMAL RECESSIVE, WITH BRACHY-SYN-POLYDACTYLY</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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ROR2, ARG441TER
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<br />
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SNP: rs267607016,
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gnomAD: rs267607016,
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ClinVar: RCV000007742, RCV000761457, RCV003441709, RCV005042009
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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>Schwarzer et al. (2009) identified homozygosity for a 1324C-T transition in the ROR2 gene, resulting in an arg441-to-ter (R441X) substitution, in a 9-month old Omani child exhibiting features of Robinow syndrome in conjunction with complex, symmetric brachy-syn-polydactyly of the hands and oligodactyly of the feet with absent toes 2 to 4 (see 268310). The Omani parents were healthy, had no features of Robinow syndrome or brachydactyly type B1 (113000), and were distantly related by mothers of the same tribal background. The mutation was located at the same position as a frameshift mutation (602337.0008) causing dominant BDB1. </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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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Nomi, M., Oishi, I., Kani, S., Suzuki, H., Matsuda, T., Yoda, A., Kitamura, M., Itoh, K., Takeuchi, S., Takeda, K., Akira, S., Ikeya, M., Takada, S., Minami, Y.
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Oishi, I., Suzuki, H., Onishi, N., Takada, R., Kani, S., Ohkawara, B., Koshida, I., Suzuki, K., Yamada, G., Schwabe, G. C., Mundlos, S., Shibuya, H., Takada, S., Minami, Y.
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Oishi, I., Takeuchi, S., Hashimoto, R., Nagabukuro, A., Ueda, T., Liu, Z.-J., Hatta, T., Akira, S., Matsuda, Y., Yamamura, H., Otani, H., Minami, Y.
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<p class="mim-text-font">
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Oldridge, M., Fortuna, A. M., Maringa, M., Propping, P., Mansour, S., Pollitt, C., DeChiara, T. M., Kimble, R. B., Valenzuela, D. M., Yancopoulos, G. D., Wilkie, A. O. M.
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<strong>Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.</strong>
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Nature Genet. 24: 275-278, 2000.
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[PubMed: 10700182]
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<p class="mim-text-font">
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Oldridge, M., Temple, I. K. Santos, H. G., Gibbons, R. J., Mustafa, Z., Chapman, K. E., Loughlin, J., Wilkie, A. O. M.
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<strong>Brachydactyly type B: linkage to chromosome 9q22 and evidence for genetic heterogeneity.</strong>
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Am. J. Hum. Genet. 64: 578-585, 1999.
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[PubMed: 9973296]
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[Full Text: https://doi.org/10.1086/302255]
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</p>
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<li>
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<p class="mim-text-font">
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Schott, G. D.
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<strong>Hereditary brachydactyly with nail dysplasia.</strong>
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J. Med. Genet. 15: 119-122, 1978.
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[PubMed: 641944]
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[Full Text: https://doi.org/10.1136/jmg.15.2.119]
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</p>
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<li>
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<p class="mim-text-font">
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|
Schott, G. D.
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<strong>Hereditary brachydactyly with nail dysplasia. (Letter)</strong>
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|
J. Med. Genet. 16: 236 only, 1979.
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[PubMed: 469906]
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[Full Text: https://doi.org/10.1136/jmg.16.3.236]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Schwabe, G. C., Tinschert, S., Buschow, C., Meinecke, P., Wolff, G., Gillessen-Kaesbach, G., Oldridge, M., Wilkie, A. O. M., Komec, R., Mundlos, S.
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<strong>Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.</strong>
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[Full Text: https://doi.org/10.1086/303084]
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Schwabe, G. C., Trepczik, B., Suring, K., Brieske, N., Tucker, A. S., Sharpe, P. T., Minami, Y., Mundlos, S.
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<strong>Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome.</strong>
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Dev. Dyn. 229: 400-410, 2004.
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[PubMed: 14745966]
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[Full Text: https://doi.org/10.1002/dvdy.10466]
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Schwarzer, W., Witte, F., Rajab, A., Mundlos, S., Stricker, S.
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<strong>A gradient of ROR2 protein stability and membrane localization confers brachydactyly type B or Robinow syndrome phenotypes.</strong>
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Hum. Molec. Genet. 18: 4013-4021, 2009.
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[PubMed: 19640924]
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[Full Text: https://doi.org/10.1093/hmg/ddp345]
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Takeuchi, S., Takeda, K., Oishi, I., Nomi, M., Ikeya, M., Itoh, K., Tamura, S., Ueda, T., Hatta, T., Otani, H., Terashima, T., Takada, S., Yamamura, H., Akira, S., Minami, Y.
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<strong>Mouse Ror2 receptor tyrosine kinase is required for the heart development and limb formation.</strong>
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Genes Cells 5: 71-78, 2000.
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[PubMed: 10651906]
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[Full Text: https://doi.org/10.1046/j.1365-2443.2000.00300.x]
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Tufan, F., Cefle, K., Turkmen, S., Turkmen, A., Zorba, U., Dursun, M., Ozturk, S., Palanduz, S., Ecder, T., Mundlos, S., Horn, D.
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<strong>Clinical and molecular characterization of two adults with autosomal recessive Robinow syndrome.</strong>
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van Bokhoven, H., Brunner, H. G.
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<strong>Splitting p63.</strong>
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Am. J. Hum. Genet. 71: 1-13, 2002. Note: Erratum: Am. J. Hum. Genet. 72: 779 only, 2003.
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[PubMed: 12037717]
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[Full Text: https://doi.org/10.1086/341450]
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van Bokhoven, H., Celli, J., Kayserili, H., van Beusekom, E., Balci, S., Brussel, W., Skovby, F., Kerr, B., Percin, E. F., Akarsu, N., Brunner, H. G.
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<strong>Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome.</strong>
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Nature Genet. 25: 423-426, 2000.
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[PubMed: 10932187]
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[Full Text: https://doi.org/10.1038/78113]
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Zhang, C., Brunt, L., Ono, Y., Rogers, S., Scholpp, S.
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<strong>Cytoneme-mediated transport of active Wnt5b-Ror2 complexes in zebrafish.</strong>
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Nature 625: 126-133, 2024.
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[PubMed: 38123680]
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[Full Text: https://doi.org/10.1038/s41586-023-06850-7]
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