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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. 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.

Original publication




Journal article


Nat Genet

Publication Date





419 - 422


Abnormalities, Multiple, Alleles, DNA, DNA Mutational Analysis, Face, Genes, Dominant, Genes, Recessive, Humans, Limb Deformities, Congenital, Molecular Sequence Data, Mutation, Polymorphism, Restriction Fragment Length, Polymorphism, Single-Stranded Conformational, Receptor Protein-Tyrosine Kinases, Receptor Tyrosine Kinase-like Orphan Receptors, Receptors, Cell Surface, Syndactyly, Syndrome