Mutation of Wnt5A in Patients with Autosomal Dominant Robinow Syndrome

Objectives: Robinow Syndrome is a heritable condition with both autosomal dominant and autosomal recessive transmission described. Both forms are characterized by short stature, mesomelic limb shortening, craniofacial abnormalities and orodental abnormalities. The recessive form has been associated with mutations in the tyrosine kinase receptor, ROR2, a putative mediator of Wnt5a signaling. Previous work in mice has shown that Wnt5a functions to promote proper craniofacial morphogenesis, limb outgrowth, and cardiac formation during embryonic development. The purpose of this study was to use candidate gene approach to identify the causative gene(s) for autosomal Dominant Robinow syndrome. Method: Twenty seven patients with autosomal dominant Robinow syndrome were identified by physicians/geneticist. Genomic DNA was isolated using a standard protocol from whole blood from affecteds and seventeen control individuals. We used 100 micrograms of DNA in PCR reactions with intronic WNT5A primer pair spanning across each individual exon for all patients and controls. Results: We have shown, using a candidate gene approach, that dominant Robinow syndrome in all affected members of the original family described by Dr. Robinow, is associated with a heterozygous missense mutation in a highly conserved region of exon 4 of WNT5A. The single living unaffected family member has two wild type WNT5A alleles. A second WNT5A mutation has been found in exon 3 in an unrelated patient with sporadic Robinow Syndrome with a dominant phenotype. Both mutant proteins show reduced function in a zebrafish cell migration assay. Conclusion: This data suggests that a WNT5A signaling pathway dependent on ROR2 for signal transduction is important in human craniofacial, skeletal and orodental development, and that normal development of these structures is sensitive to variations in WNT5A function.