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

Abstract

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.

Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome

“…In humans, ROR2 mutations account for autosomal recessive Robinow syndrome (Afzal et al, 2000;van Bokhoven et al, 2000;RS, MIM 268310) and autosomal dominant brachydactyly type B Schwabe et al, 2000; BDB, MIM 113000), two distinct human malformation syndromes. Robinow syndrome is a multisystemic disease, characterized by moderate shortness of stature, mesomelic limb shortening, hemivertebrae, genital hypoplasia, and a characteristic facial appearance (for review see Patton and Afzal, 2002).…”

Cloning and expression pattern of chicken Ror2 and functional characterization of truncating mutations in Brachydactyly type B and Robinow syndrome

“…BDB is a human limb malformation syndrome characterized by hypoplasia and/or aplasia of distal phalanges. Furthermore, mutations in ROR2 are causative for a very distinct syndrome, autosomal recessive Robinow syndrome (RS, MIM268310; Afzal et al, 2000;van Bokhoven et al, 2000). RS is characterized by short stature, mesomelic limb shortening, hemivertebrae, genital hypoplasia, and characteristic facial features (Patton and Afzal, 2002).…”

A novel single-base deletion in ROR2 causes atypical brachydactyly type B1 with cutaneous syndactyly in a large Chinese family

“…1 Heterozygous gain-of-function mutations in ROR2 are responsible for the autosomal dominant brachydactyly type B1 (BDB1; MIM 113000), whereas homozygous loss-of-function mutations in ROR2 lead to autosomal recessive Robinow syndrome (MIM 268310). [2][3][4][5] BDB1 is the most severe type of human brachydactylies, and shows high penetrance and variable expression. Hypoplastic or absent distal phalanges and nails of digits 2-5 in the hands and feet are cardinal phenotypic features of BDB1.…”

“…2 In contrast, Robinow syndrome presents with short stature, short limbs, brachydactyly, hemivertebrae, rib fusion, genital hypoplasia and a characteristic facial appearance. 4,5 Many ROR2 mutations have been reported in patients with BDB1 and the autosomal recessive form of Robinow syndrome. [1][2][3][4][5][6][7][8] However, only the c.2249delG (p.G750fsX23) mutation was found to cause atypical and severe BDB1 associated with cutaneous syndactyly.…”

“…4,5 Many ROR2 mutations have been reported in patients with BDB1 and the autosomal recessive form of Robinow syndrome. [1][2][3][4][5][6][7][8] However, only the c.2249delG (p.G750fsX23) mutation was found to cause atypical and severe BDB1 associated with cutaneous syndactyly. 2 Here, we report a new single-base deletion of the ROR2 gene in a large Chinese family with the BDB1-syndactyly phenotype.…”