Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome

Robinow syndrome is a short-limbed dwarfism characterized by abnormal morph ogenesis of the face and external genitalia, and vertebral segmentation(1,2 ). The recessive form of Robinow syndrome (RRS; OMIM 268310). particularly frequent in Turkey(3-6), has a high incidence of abnormalities of the verte bral column such as hemivertebrae and rib fusions. which is not seen in the dominant form. Some patients have cardiac malformations or facial clefting . We have mapped a gene for RRS to 9q21-q23 in 11 families. Haplotype shari ng was observed between three families from Turkey, which localized the gen e to a 4.9-cM interval. The gene ROR2, which encodes an orphan membrane-bou nd tyrosine kinase, maps to this region. Heterozygous (presumed gain of fun ction) mutations in ROR2 were previously shown to cause dominant brachydact yly type B (BDB; ref. 7). In contrast, Ror2(-/-) mice have a short-limbed p henotype that is more reminiscent of the mesomelic shortening observed in R RS. We detected several homozygous ROR2 mutations in our cohort of RRS pati ents that are located upstream from those previously found in BDB. The ROR2 mutations present in RRS result in premature stop codons and predict nonfu nctional proteins.