Distinct Mutations in the Receptor Tyrosine Kinase Gene ROR2 Cause Brachydactyly Type B
Brachydactyly type B (BDB) is an autosomal dominant skeletal disorder characterized by hypoplasia/aplasia of distal phalanges and nails. Recently, heterozygous mutations of the orphan receptor tyrosine kinase (TK) ROR2, located within a distinct segment directly after the TK domain, have been shown...
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creator | Schwabe, Georg C. Tinschert, Sigrid Buschow, Christian Meinecke, Peter Wolff, Gerhard Gillessen-Kaesbach, Gabriele Oldridge, Michael Wilkie, Andrew O.M. Kömec, Reyhan Mundlos, Stefan |
description | Brachydactyly type B (BDB) is an autosomal dominant skeletal disorder characterized by hypoplasia/aplasia of distal phalanges and nails. Recently, heterozygous mutations of the orphan receptor tyrosine kinase (TK)
ROR2, located within a distinct segment directly after the TK domain, have been shown to be responsible for BDB. We report four novel mutations in
ROR2 (two frameshifts, one splice mutation, and one nonsense mutation) in five families with BDB. The mutations predict truncation of the protein within two distinct regions immediately before and after the TK domain, resulting in a complete or partial loss of the intracellular portion of the protein. Patients affected with the distal mutations have a more severe phenotype than do those with the proximal mutation. Our analysis includes the first description of homozygous BDB in an individual with a 5-bp deletion proximal to the TK domain. His phenotype resembles an extreme form of brachydactyly, with extensive hypoplasia of the phalanges and metacarpals/metatarsals and absence of nails. In addition, he has vertebral anomalies, brachymelia of the arms, and a ventricular septal defect—features that are reminiscent of Robinow syndrome, which has also been shown to be caused by mutations in
ROR2. The BDB phenotype, as well as the location and the nature of the BDB mutations, suggests a specific mutational effect that cannot be explained by simple haploinsufficiency and that is distinct from that in Robinow syndrome. |
doi_str_mv | 10.1086/303084 |
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ROR2, located within a distinct segment directly after the TK domain, have been shown to be responsible for BDB. We report four novel mutations in
ROR2 (two frameshifts, one splice mutation, and one nonsense mutation) in five families with BDB. The mutations predict truncation of the protein within two distinct regions immediately before and after the TK domain, resulting in a complete or partial loss of the intracellular portion of the protein. Patients affected with the distal mutations have a more severe phenotype than do those with the proximal mutation. Our analysis includes the first description of homozygous BDB in an individual with a 5-bp deletion proximal to the TK domain. His phenotype resembles an extreme form of brachydactyly, with extensive hypoplasia of the phalanges and metacarpals/metatarsals and absence of nails. In addition, he has vertebral anomalies, brachymelia of the arms, and a ventricular septal defect—features that are reminiscent of Robinow syndrome, which has also been shown to be caused by mutations in
ROR2. The BDB phenotype, as well as the location and the nature of the BDB mutations, suggests a specific mutational effect that cannot be explained by simple haploinsufficiency and that is distinct from that in Robinow syndrome.</description><identifier>ISSN: 0002-9297</identifier><identifier>EISSN: 1537-6605</identifier><identifier>DOI: 10.1086/303084</identifier><identifier>PMID: 10986040</identifier><identifier>CODEN: AJHGAG</identifier><language>eng</language><publisher>Chicago, IL: Elsevier Inc</publisher><subject>Amino Acid Sequence ; Base Sequence ; Biological and medical sciences ; Codon, Nonsense - genetics ; Consanguinity ; Diseases of the osteoarticular system ; DNA Mutational Analysis ; Exons - genetics ; Female ; Fingers - abnormalities ; Fingers - physiopathology ; Frameshift Mutation - genetics ; Genotype ; Hand Deformities, Congenital - classification ; Hand Deformities, Congenital - genetics ; Hand Deformities, Congenital - physiopathology ; Humans ; Introns - genetics ; Male ; Malformations and congenital and or hereditary diseases involving bones. Joint deformations ; Medical sciences ; Molecular Sequence Data ; Mutation - genetics ; Pedigree ; Phenotype ; Protein Structure, Tertiary ; Receptor Protein-Tyrosine Kinases - genetics ; Receptor Tyrosine Kinase-like Orphan Receptors ; Receptors, Cell Surface - chemistry ; Receptors, Cell Surface - genetics ; RNA Splice Sites - genetics ; Syndrome</subject><ispartof>American journal of human genetics, 2000-10, Vol.67 (4), p.822-831</ispartof><rights>2000 The American Society of Human Genetics</rights><rights>2000 INIST-CNRS</rights><rights>2000 by The American Society of Human Genetics. All rights reserved. 2000</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c434t-39a9279fd2d9c133160f2b7905c93825861922cea9e0c139960bc80911a4e8a93</citedby><cites>FETCH-LOGICAL-c434t-39a9279fd2d9c133160f2b7905c93825861922cea9e0c139960bc80911a4e8a93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1287887/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://dx.doi.org/10.1086/303084$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,3550,27924,27925,45995,53791,53793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1507544$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10986040$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schwabe, Georg C.</creatorcontrib><creatorcontrib>Tinschert, Sigrid</creatorcontrib><creatorcontrib>Buschow, Christian</creatorcontrib><creatorcontrib>Meinecke, Peter</creatorcontrib><creatorcontrib>Wolff, Gerhard</creatorcontrib><creatorcontrib>Gillessen-Kaesbach, Gabriele</creatorcontrib><creatorcontrib>Oldridge, Michael</creatorcontrib><creatorcontrib>Wilkie, Andrew O.M.</creatorcontrib><creatorcontrib>Kömec, Reyhan</creatorcontrib><creatorcontrib>Mundlos, Stefan</creatorcontrib><title>Distinct Mutations in the Receptor Tyrosine Kinase Gene ROR2 Cause Brachydactyly Type B</title><title>American journal of human genetics</title><addtitle>Am J Hum Genet</addtitle><description>Brachydactyly type B (BDB) is an autosomal dominant skeletal disorder characterized by hypoplasia/aplasia of distal phalanges and nails. Recently, heterozygous mutations of the orphan receptor tyrosine kinase (TK)
ROR2, located within a distinct segment directly after the TK domain, have been shown to be responsible for BDB. We report four novel mutations in
ROR2 (two frameshifts, one splice mutation, and one nonsense mutation) in five families with BDB. The mutations predict truncation of the protein within two distinct regions immediately before and after the TK domain, resulting in a complete or partial loss of the intracellular portion of the protein. Patients affected with the distal mutations have a more severe phenotype than do those with the proximal mutation. Our analysis includes the first description of homozygous BDB in an individual with a 5-bp deletion proximal to the TK domain. His phenotype resembles an extreme form of brachydactyly, with extensive hypoplasia of the phalanges and metacarpals/metatarsals and absence of nails. In addition, he has vertebral anomalies, brachymelia of the arms, and a ventricular septal defect—features that are reminiscent of Robinow syndrome, which has also been shown to be caused by mutations in
ROR2. The BDB phenotype, as well as the location and the nature of the BDB mutations, suggests a specific mutational effect that cannot be explained by simple haploinsufficiency and that is distinct from that in Robinow syndrome.</description><subject>Amino Acid Sequence</subject><subject>Base Sequence</subject><subject>Biological and medical sciences</subject><subject>Codon, Nonsense - genetics</subject><subject>Consanguinity</subject><subject>Diseases of the osteoarticular system</subject><subject>DNA Mutational Analysis</subject><subject>Exons - genetics</subject><subject>Female</subject><subject>Fingers - abnormalities</subject><subject>Fingers - physiopathology</subject><subject>Frameshift Mutation - genetics</subject><subject>Genotype</subject><subject>Hand Deformities, Congenital - classification</subject><subject>Hand Deformities, Congenital - genetics</subject><subject>Hand Deformities, Congenital - physiopathology</subject><subject>Humans</subject><subject>Introns - genetics</subject><subject>Male</subject><subject>Malformations and congenital and or hereditary diseases involving bones. Joint deformations</subject><subject>Medical sciences</subject><subject>Molecular Sequence Data</subject><subject>Mutation - genetics</subject><subject>Pedigree</subject><subject>Phenotype</subject><subject>Protein Structure, Tertiary</subject><subject>Receptor Protein-Tyrosine Kinases - genetics</subject><subject>Receptor Tyrosine Kinase-like Orphan Receptors</subject><subject>Receptors, Cell Surface - chemistry</subject><subject>Receptors, Cell Surface - genetics</subject><subject>RNA Splice Sites - genetics</subject><subject>Syndrome</subject><issn>0002-9297</issn><issn>1537-6605</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU1v1DAQhq0KRJcWfkKVA-IWGNv5sC-VygIF0arSqoijNetMWFdZZ7GdSvn3uNpVWzjN16N3Ru8w9pbDBw6q-ShBgqqO2ILXsi2bBuoXbAEAotRCt8fsdYx3AJwrkK_YMQetGqhgwX59djE5b1NxPSVMbvSxcL5IGypWZGmXxlDczmGMzlPxw3mMVFxSzlc3K1Esccr1p4B2M3do0zzMmd7l1il72eMQ6c0hnrCfX7_cLr-VVzeX35cXV6WtZJVKqVGLVved6LTlUvIGerFuNdRWSyVq1XAthCXUBHmudQNrq0BzjhUp1PKEne91d9N6S50lnwIOZhfcFsNsRnTm34l3G_N7vDdcqFapNgu8PwiE8c9EMZmti5aGAT2NUzStEI2o6voJtNmNGKh_XMLBPPzA7H-QwbPnJz3D9qZn4N0BwGhx6AN66-ITV0NbVw86sMco-3fvKJhoHXlLnQtkk-lG9__qvyIwnLs</recordid><startdate>20001001</startdate><enddate>20001001</enddate><creator>Schwabe, Georg C.</creator><creator>Tinschert, Sigrid</creator><creator>Buschow, Christian</creator><creator>Meinecke, Peter</creator><creator>Wolff, Gerhard</creator><creator>Gillessen-Kaesbach, Gabriele</creator><creator>Oldridge, Michael</creator><creator>Wilkie, Andrew O.M.</creator><creator>Kömec, Reyhan</creator><creator>Mundlos, Stefan</creator><general>Elsevier Inc</general><general>University of Chicago Press</general><general>The American Society of Human Genetics</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20001001</creationdate><title>Distinct Mutations in the Receptor Tyrosine Kinase Gene ROR2 Cause Brachydactyly Type B</title><author>Schwabe, Georg C. ; Tinschert, Sigrid ; Buschow, Christian ; Meinecke, Peter ; Wolff, Gerhard ; Gillessen-Kaesbach, Gabriele ; Oldridge, Michael ; Wilkie, Andrew O.M. ; Kömec, Reyhan ; Mundlos, Stefan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c434t-39a9279fd2d9c133160f2b7905c93825861922cea9e0c139960bc80911a4e8a93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Amino Acid Sequence</topic><topic>Base Sequence</topic><topic>Biological and medical sciences</topic><topic>Codon, Nonsense - genetics</topic><topic>Consanguinity</topic><topic>Diseases of the osteoarticular system</topic><topic>DNA Mutational Analysis</topic><topic>Exons - genetics</topic><topic>Female</topic><topic>Fingers - abnormalities</topic><topic>Fingers - physiopathology</topic><topic>Frameshift Mutation - genetics</topic><topic>Genotype</topic><topic>Hand Deformities, Congenital - classification</topic><topic>Hand Deformities, Congenital - genetics</topic><topic>Hand Deformities, Congenital - physiopathology</topic><topic>Humans</topic><topic>Introns - genetics</topic><topic>Male</topic><topic>Malformations and congenital and or hereditary diseases involving bones. Joint deformations</topic><topic>Medical sciences</topic><topic>Molecular Sequence Data</topic><topic>Mutation - genetics</topic><topic>Pedigree</topic><topic>Phenotype</topic><topic>Protein Structure, Tertiary</topic><topic>Receptor Protein-Tyrosine Kinases - genetics</topic><topic>Receptor Tyrosine Kinase-like Orphan Receptors</topic><topic>Receptors, Cell Surface - chemistry</topic><topic>Receptors, Cell Surface - genetics</topic><topic>RNA Splice Sites - genetics</topic><topic>Syndrome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schwabe, Georg C.</creatorcontrib><creatorcontrib>Tinschert, Sigrid</creatorcontrib><creatorcontrib>Buschow, Christian</creatorcontrib><creatorcontrib>Meinecke, Peter</creatorcontrib><creatorcontrib>Wolff, Gerhard</creatorcontrib><creatorcontrib>Gillessen-Kaesbach, Gabriele</creatorcontrib><creatorcontrib>Oldridge, Michael</creatorcontrib><creatorcontrib>Wilkie, Andrew O.M.</creatorcontrib><creatorcontrib>Kömec, Reyhan</creatorcontrib><creatorcontrib>Mundlos, Stefan</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of human genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schwabe, Georg C.</au><au>Tinschert, Sigrid</au><au>Buschow, Christian</au><au>Meinecke, Peter</au><au>Wolff, Gerhard</au><au>Gillessen-Kaesbach, Gabriele</au><au>Oldridge, Michael</au><au>Wilkie, Andrew O.M.</au><au>Kömec, Reyhan</au><au>Mundlos, Stefan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Distinct Mutations in the Receptor Tyrosine Kinase Gene ROR2 Cause Brachydactyly Type B</atitle><jtitle>American journal of human genetics</jtitle><addtitle>Am J Hum Genet</addtitle><date>2000-10-01</date><risdate>2000</risdate><volume>67</volume><issue>4</issue><spage>822</spage><epage>831</epage><pages>822-831</pages><issn>0002-9297</issn><eissn>1537-6605</eissn><coden>AJHGAG</coden><abstract>Brachydactyly type B (BDB) is an autosomal dominant skeletal disorder characterized by hypoplasia/aplasia of distal phalanges and nails. Recently, heterozygous mutations of the orphan receptor tyrosine kinase (TK)
ROR2, located within a distinct segment directly after the TK domain, have been shown to be responsible for BDB. We report four novel mutations in
ROR2 (two frameshifts, one splice mutation, and one nonsense mutation) in five families with BDB. The mutations predict truncation of the protein within two distinct regions immediately before and after the TK domain, resulting in a complete or partial loss of the intracellular portion of the protein. Patients affected with the distal mutations have a more severe phenotype than do those with the proximal mutation. Our analysis includes the first description of homozygous BDB in an individual with a 5-bp deletion proximal to the TK domain. His phenotype resembles an extreme form of brachydactyly, with extensive hypoplasia of the phalanges and metacarpals/metatarsals and absence of nails. In addition, he has vertebral anomalies, brachymelia of the arms, and a ventricular septal defect—features that are reminiscent of Robinow syndrome, which has also been shown to be caused by mutations in
ROR2. The BDB phenotype, as well as the location and the nature of the BDB mutations, suggests a specific mutational effect that cannot be explained by simple haploinsufficiency and that is distinct from that in Robinow syndrome.</abstract><cop>Chicago, IL</cop><pub>Elsevier Inc</pub><pmid>10986040</pmid><doi>10.1086/303084</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Amino Acid Sequence Base Sequence Biological and medical sciences Codon, Nonsense - genetics Consanguinity Diseases of the osteoarticular system DNA Mutational Analysis Exons - genetics Female Fingers - abnormalities Fingers - physiopathology Frameshift Mutation - genetics Genotype Hand Deformities, Congenital - classification Hand Deformities, Congenital - genetics Hand Deformities, Congenital - physiopathology Humans Introns - genetics Male Malformations and congenital and or hereditary diseases involving bones. Joint deformations Medical sciences Molecular Sequence Data Mutation - genetics Pedigree Phenotype Protein Structure, Tertiary Receptor Protein-Tyrosine Kinases - genetics Receptor Tyrosine Kinase-like Orphan Receptors Receptors, Cell Surface - chemistry Receptors, Cell Surface - genetics RNA Splice Sites - genetics Syndrome |
title | Distinct Mutations in the Receptor Tyrosine Kinase Gene ROR2 Cause Brachydactyly Type B |
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