Mutations in DVL1 Cause an Osteosclerotic Form of Robinow Syndrome

Abstract

Robinow syndrome (RS) is a phenotypically and genetically heterogeneous condition that can be caused by mutations in genes encoding components of the non-canonical Wnt signaling pathway. In contrast, germline mutations that act to increase canonical Wnt signaling lead to distinctive osteosclerotic phenotypes. Here, we identified de novo frameshift mutations in DVL1, a mediator of both canonical and non-canonical Wnt signaling, as the cause of RS-OS, an RS subtype involving osteosclerosis, in three unrelated individuals. The mutations all delete the DVL1 C terminus and replace it, in each instance, with a novel, highly basic sequence. We showed the presence of mutant transcript in fibroblasts from one individual with RS-OS and demonstrated unimpaired protein stability with transfected GFP-tagged constructs bearing a frameshift mutation. In vitro TOPFlash assays, in apparent contradiction to the osteosclerotic phenotype, revealed that the mutant allele was less active than the wild-type allele in the canonical Wnt signaling pathway. However, when the mutant and wild-type alleles were co-expressed, canonical Wnt activity was 2-fold higher than that in the wild-type construct alone. This work establishes that DVL1 mutations cause a specific RS subtype, RS-OS, and that the osteosclerosis associated with this subtype might be the result of an interaction between the wild-type and mutant alleles and thus lead to elevated canonical Wnt signaling.

Dishevelled: A masterful conductor of complex Wnt signals

“…Another study indicates that frameshift mutation on exon 15 replaces the C-terminal tail of DVL-1 with 142 highly basic amino acid. And these de-novo mutations on DVL-1 result in osteosclerotic form of Robinow syndrome [187]. To summarize, DVL plays an important role in development processes and mutations in DVL gene can lead to severe phenotypic defects.…”

A genetic signature of the evolution of loss of flight in the Galapagos cormorant

“…Fat1 knockout mice show very selective defects in muscles of the upper body, but not in posterior muscles (54). In addition, Dvl1 is mutated in humans with Robinow syndrome, characterized by limb shortening (55, 56). …”

Genetics of Short Stature

“…The intracellular defects are highly heterogeneous, such as RAS (rat sarcoma)-MAPK (mitogen-activated protein kinase) pathway [9–20], guanine nucleotide exchange factor [21–23], cyclic AMP (cAMP) dependent regulatory subunit of protein kinase A [24], and other signaling proteins [25–32]. Especially, altered RAS-MAPK signaling has been identified as a key pathway in regulation of growth plate chondrogenesis and is affected in several disorders, referred to as RASopathies [33].…”

“…Mutations in these genes may not only result in skeletal dysplasias but also variable hormone resistance, thus demonstrating the important role of this pathway both in the regulation of growth plate chondrogenesis and in signaling of the G-protein coupled hormone receptors [25]. In addition, defects in the WNT5A/JNK signaling pathway including mutations in ROR2, DVL1 as well as Wnt5a, the ligand of ROR2 , cause skeletal dysplasia, Robinow syndrome characterized by dysmorphic facial features, frontal bossing, hypertelorism, broad nose, short-limbed dwarfism, vertebral segmentation, and genital hypoplasia [29–32]. …”