Distinct Mutations in the Receptor Tyrosine Kinase Gene ROR2 Cause Brachydactyly Type B

Abstract

Brachydactyly type B (BDB) is an autosomal dominant skeletal disorder characterized by hypoplasia/aplasia of distal phalanges and nails. Recently, heterozygous mutations of the orphan receptor tyrosine kinase (TK) ROR2, located within a distinct segment directly after the TK domain, have been shown to be responsible for BDB. We report four novel mutations in ROR2 (two frameshifts, one splice mutation, and one nonsense mutation) in five families with BDB. The mutations predict truncation of the protein within two distinct regions immediately before and after the TK domain, resulting in a complete or partial loss of the intracellular portion of the protein. Patients affected with the distal mutations have a more severe phenotype than do those with the proximal mutation. Our analysis includes the first description of homozygous BDB in an individual with a 5-bp deletion proximal to the TK domain. His phenotype resembles an extreme form of brachydactyly, with extensive hypoplasia of the phalanges and metacarpals/metatarsals and absence of nails. In addition, he has vertebral anomalies, brachymelia of the arms, and a ventricular septal defect-features that are reminiscent of Robinow syndrome, which has also been shown to be caused by mutations in ROR2. The BDB phenotype, as well as the location and the nature of the BDB mutations, suggests a specific mutational effect that cannot be explained by simple haploinsufficiency and that is distinct from that in Robinow syndrome.

Mechanisms of digit formation: Human malformation syndromes tell the story

“…3). BDB1 is caused by mutations in ROR2 and results in hypoplastic/absent terminal phalanges Schwabe et al, 2000). ROR2 encodes a receptor tyrosine kinase (Masiakowski and Carroll, 1992).…”

“…This is often combined with distal symphalangism in the milder cases. The BDB1 phenotypes correlate with the type and position of the mutation (Schwabe et al, 2000) and are caused by differential stability and intracellular localization of the resulting truncated protein product (Schwarzer et al, 2009). Witte et al (2010b) analyzed mouse mutants harboring a targeted insertion of a human mutation in the endogenous Ror2 locus (Ror2 p.W749X), causing severe BDB1 phenotypes.…”

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).…”

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.…”

“…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.…”