The mutationROR2W749X, linked to human BDB, is a recessive mutation in the mouse, causing brachydactyly, mediating patterning of joints and modeling recessive Robinow syndrome

Abstract

Mutations in ROR2 result in a spectrum of genetic disorders in humans that are classified, depending on the nature of the mutation and the clinical phenotype, as either autosomal dominant brachydactyly type B (BDB, MIM 113000) or recessive Robinow syndrome (RRS, MIM 268310). In an attempt to model BDB in mice, the mutation W749X was engineered into the mouse Ror2 gene. In contrast to the human situation, mice heterozygous for Ror2 W749FLAG are normal and do not develop brachydactyly, whereas homozygous mice exhibit features resembling RRS. Furthermore, both Ror2 W749FLAG/W749FLAG and a previously engineered mutant, Ror2 TMlacZ/TMlacZ , lack the P2/P3 joint. Absence of Gdf5 expression at the corresponding interzone suggests that the defect is in specification of the joint. As this phenotype is absent in mice lacking the entire Ror2 gene, it appears that specification of the P2/P3 joint is affected by ROR2 activity. Finally, Ror2 W749FLAG/W749FLAG mice survive to adulthood and exhibit phenotypes (altered body composition, reduced male fertility) not observed in Ror2 knockout mice, presumably due to the perinatal lethality of the latter. Therefore, Ror2 W749FLAG/W749FLAG mice represent a postnatal model for RRS, provide insight into the mechanism of joint specification, and uncover novel roles of Ror2 in the mouse.

Receptor tyrosine kinase-like orphan receptor 2 (ROR2) and Indian hedgehog regulate digit outgrowth mediated by the phalanx-forming region

“…premature regression of the AER was observed in Ror2 W749X/W749X or Ihh E95K/E95K mice (6,9). At E14.5, the remaining distal cartilage is undergoing the program for tip formation in Ror2 W749X/W749X mice, at the appropriate time as in WT mice, concordant with a reactivation of Ihh expression.…”

Loss of Wnt5a Disrupts Primordial Germ Cell Migration and Male Sexual Development in Mice1

“…On the other hand, there are, to our knowledge, no reports of recessive Robinow syndrome male patients having reproduced (reviewed in Patton and Afzal [73]). Importantly, knockin mice harboring a ROR2 W749X mutation have been shown to model adult recessive Robinow syndrome, and adult male mice display reduced fertility [77]. Adult testes from ROR2 W749X homozygous males were smaller than those of wild-type, a phenotype caused by focal degeneration of seminiferous tubules with reduced number of spermatogonia and lack of spermatocytes [77].…”

Mechanisms of digit formation: Human malformation syndromes tell the story

“…This phenotype, presence of a terminal phalanx but absence of more proximal structures is seen in human brachydactylies type A1, A2 and in some cases of BDB1. However, analyses of mouse models for BDA1 and BDB1 (Raz et al, 2008;Gao et al, 2009) have found no indication of AER/Fgf involvement in the pathogenesis of these syndromes. It thus appeared likely that another mechanism must be involved in the elongation of the digits, namely by driving chondrogenesis in a distally orientated manner.…”

“…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. Homozygous Ror W749X/W749X mice lack the medial phalanges, this phenotype has previously been considered to be a defect in the formation of the last interphalangeal joint (Raz et al, 2008). Witte et al (2010b) showed that preceding the failure of joint formation, elongation of the phalangeal condensation was severely impaired.…”