Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome

Am J Hum Genet. 2015 Apr 2;96(4):623-30. doi: 10.1016/j.ajhg.2015.02.010. Epub 2015 Mar 26.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Craniofacial Abnormalities / genetics*
  • Craniofacial Abnormalities / pathology*
  • Dishevelled Proteins
  • Dwarfism / genetics*
  • Dwarfism / pathology*
  • Frameshift Mutation / genetics*
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Limb Deformities, Congenital / genetics*
  • Limb Deformities, Congenital / pathology*
  • Osteosclerosis / genetics*
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Urogenital Abnormalities / genetics*
  • Urogenital Abnormalities / pathology*
  • Wnt Signaling Pathway / genetics*


  • Adaptor Proteins, Signal Transducing
  • DVL1 protein, human
  • Dishevelled Proteins
  • Phosphoproteins
  • Green Fluorescent Proteins

Supplementary concepts

  • Robinow Syndrome