Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2

• Published in: Nature genetics Vol. 25; no. 4; pp. 419 - 422
• Main Authors: Afzal, Ali R., Rajab, Anna, Fenske, Christiane D., Oldridge, Michael, Elanko, Navaratnam, Ternes-Pereira, Eliana, Tüysüz, Beyhan, Murday, Victoria A., Patton, Michael A., Wilkie, Andrew O.M., Jeffery, Steve
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2000; Nature Publishing Group
• Subjects: Abnormalities, Multiple - genetics; Abnormalities, Multiple - pathology; Agriculture; Alleles; Analysis; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; brachydactyly; Cancer Research; chromosome 9; Chromosomes; Classical genetics, quantitative genetics, hybrids; Development and progression; Diseases of the osteoarticular system; DNA - chemistry; DNA - genetics; DNA Mutational Analysis; Face - abnormalities; Fundamental and applied biological sciences. Psychology; Gene Function; Gene mutations; Genes, Dominant; Genes, Recessive; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Human; Human Genetics; Humans; Kinases; letter; Limb Deformities, Congenital - genetics; Limb Deformities, Congenital - pathology; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Molecular Sequence Data; Mutation; Polymorphism, Restriction Fragment Length; Polymorphism, Single-Stranded Conformational; Proteins; Receptor Protein-Tyrosine Kinases - genetics; Receptor Tyrosine Kinase-like Orphan Receptors; Receptors, Cell Surface - genetics; Robinow syndrome; Robinow's syndrome; ROR2 gene; Spine; Syndactyly; Syndrome; United Kingdom > UK; Brazil; Oman; Case study; Human; Missense mutation; Enzyme; Nonsense mutation; Transferases; Diseases of the osteoarticular system; Robinow syndrome; Osteochondrodysplasia; Protein-tyrosine kinase; Structure function relationship; Orphan receptor
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/78107

The autosomal recessive form of Robinow syndrome (RRS; MIM 268310) is a severe skeletal dysplasia with generalized limb bone shortening, segmental defects of the spine, brachydactyly and a dysmorphic facial appearance 1 , 2 , 3 . We previously mapped the gene mutated in RRS to chromosome 9q22 (ref. 4 ), a region that overlaps the locus for autosomal dominant brachydactyly type B (refs 5 , 6 ). The recent identification of ROR2 , encoding an orphan receptor tyrosine kinase, as the gene mutated in brachydactyly type B (BDB1; ref. 7 ) and the mesomelic dwarfing in mice homozygous for a lacZ and/or a neo insertion into Ror2 (refs 8 , 9 ) made this gene a candidate for RRS. Here we report homozygous missense mutations in both intracellular and extracellular domains of ROR2 in affected individuals from 3 unrelated consanguineous families, and a nonsense mutation that removes the tyrosine kinase domain and all subsequent 3′ regions of the gene in 14 patients from 7 families from Oman. The nature of these mutations suggests that RRS is caused by loss of ROR2 activity. The identification of mutations in three distinct domains (containing Frizzled-like, kringle and tyrosine kinase motifs) indicates that these are all essential for ROR2 function.