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

Abstract

Robinow syndrome is a short-limbed dwarfism characterized by abnormal morphogenesis of the face and external genitalia, and vertebral segmentation. The recessive form of Robinow syndrome (RRS; OMIM 268310), particularly frequent in Turkey, 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.

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).…”

Clinical utility gene card for: Aarskog–Scott Syndrome (faciogenital dysplasia) – update 2015

“…However, as differences may not always be obvious, a possible targeted NGS approach in similar cases might be indicated and, in addiction to FGD1, should also include ROR2 and WNT5A, genes known to be involved in the pathogenesis of the Robinow syndrome. 16,17 …”

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.…”