Monos6-Vettese.pdf.txt

Abstract

The RASopathies are a collection of clinically similar developmental disorders characterized by congenital heart defects, craniofacial anomalies, growth defects, cognitive impairment, and a predisposition to develop cancer. These developmental disorders are caused by dysregulation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway, which is critically involved in a variety of cellular processes required for organismal development and morphogenesis. Germline mutations in components of the RAS/MAPK pathway have been associated with RASopathies; however, a notable fraction of patients with RASopathy or RASopathy-like disease do not have mutations associated with a specific RASopathy disorder. Recently, germline mutations in the RRAS2 gene, a GTPase with high similarity to Ras, were reported to be associated with Noonan syndrome. This study analyzes the phenotypic effect of a novel potential pathogenic variant in the RRAS2 gene, A158G, using zebrafish as a model organism. Zebrafish larvae overexpressing RRAS2A158G showed growth defects, reduced body length, delayed cardiac development with laterality defects, craniofacial anomalies, and pigmentation defects. The phenotypes observed in these zebrafish models are comparable to the symptoms of patients with RASopathy disorders and are consistent with the phenotypes observed in zebrafish models of RASopathies, notably Noonan syndrome. These findings indicate that the A158G mutation in the RRAS2 gene induces developmental defects in zebrafish embryos and is a likely cause of the RASopathy-like disorder observed in the patient with this specific mutation.