Mechanistic studies in Drosophila and chicken give new insights into functions of DVL1 in dominant Robinow Syndrome.

The study of rare genetic diseases provides valuable insights into human gene function. The autosomal dominant or autosomal recessive forms of Robinow Syndrome (RS) are genetically heterogeneous, and the common theme is that all the mutations lie in genes in Wnt signaling pathways. Cases diagnosed with RS do survive to adulthood with distinct skeletal phenotypes including limb shortening and craniofacial abnormalities. Here we focus on mutations in Dishevelled1 (DVL1), an intracellular adaptor protein that is required for both canonical (β-catenin-dependent) or non-canonical Wnt signaling (requiring small GTPases and JNK). We expressed human wild-type or DVL1 variants alongside the endogenous genome of the chicken and Drosophila. This design is strategically suited to test for functional differences between mutant and wild-type human proteins in relevant developmental contexts. The expression of variant forms of DVL1 produced a major disorganization of cartilage and Drosophila wing morphology compared to wtDVL1. Moreover, the variants caused a loss of canonical and gain of non-canonical Wnt signaling in several assays. Our data points to future therapies that correct the levels of Wnt signaling thus improving skeletal growth.