Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2.
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.
Medical Genetics Unit, St George's Hospital Medical School, London, UK.
A R
AR
Afzal
A
A
Rajab
C D
CD
Fenske
M
M
Oldridge
N
N
Elanko
E
E
Ternes-Pereira
B
B
Tüysüz
V A
VA
Murday
M A
MA
Patton
A O
AO
Wilkie
S
S
Jeffery
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000483:Alleles; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005145:Face / Q000002:abnormalities; D005799:Genes, Dominant; D005808:Genes, Recessive; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D011956:Receptors, Cell Surface / Q000235:genetics*; D013576:Syndactyly; D013577:Syndrome
D011956:Receptors, Cell Surface; D004247:DNA; C078717:ROR2 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D057050:Receptor Tyrosine Kinase-like Orphan Receptors