Abstract
Robinow syndrome is a short-limbed dwarfism characterized by abnormal morphogenesis of the face and external genitalia, and vertebral segmentation1,2. The recessive form of Robinow syndrome (RRS; OMIM 268310), particularly frequent in Turkey3,4,5,6, has a high incidence of abnormalities of the vertebral 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 sharing was observed between three families from Turkey, which localized the gene to a 4.9-cM interval. The gene ROR2, which encodes an orphan membrane-bound tyrosine kinase, maps to this region. Heterozygous (presumed gain of function) mutations in ROR2 were previously shown to cause dominant brachydactyly type B (BDB; ref. 7). In contrast, Ror2−/− mice have a short-limbed phenotype that is more reminiscent of the mesomelic shortening observed in RRS. We detected several homozygous ROR2 mutations in our cohort of RRS patients that are located upstream from those previously found in BDB. The ROR2 mutations present in RRS result in premature stop codons and predict nonfunctional proteins.
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Acknowledgements
We thank E. Bosgoed for technical assistance; M.A.M. van Steensel for discussions; and A. Wilkie for sharing genomic sequence data for ROR2. This work was supported by grants from the Dutch Foundation for Scientific Research (NWO) and by the Jan Dekker/Lutgardine Bouwman stichting.
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van Bokhoven, H., Celli, J., Kayserili, H. et al. Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome. Nat Genet 25, 423–426 (2000). https://doi.org/10.1038/78113
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DOI: https://doi.org/10.1038/78113
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