Mutations in DVL1 Cause an Osteosclerotic Form of Robinow Syndrome

Kieran J. Bunn, Phil Daniel, Heleen S. Roesken, Adam C. O'Neill, Sophia R. Cameron-Christie, Tim Morgan, Han G. Brunner, Angeline Lai, Henricus P. M. Kunst, David M. Markie, Stephen P. Robertson*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Pages (from-to)623-630
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - 2 Apr 2015


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