The protein encoded by RRAS2 is a ubiquitously expressed small GTPase with an important function as a signal transducer in the cell. Disturbances in signaling cascades controlling the cell’s reaction to extracellular stimuli are the underlying cause of various disorders affecting development. The RAS-MAPK pathway is one of these central signaling cascades and its upregulation results, among others, in Noonan syndrome, a developmental disorder with distinctive craniofacial appearance, congenital heart defect, short stature, variable cognitive impairment and a predisposition to malignancies. Mutations in more than 10 genes have been described as causing this syndrome, but still about 10 % of patients with clinically suspected Noonan syndrome carry no mutation in known genes associated with RASopathies.

Somatic mutations in RRAS2 have previously been associated with the growth of certain tumors. Now, the American Journal of Human Genetics reports on new insights into RRAS2. Two recent studies describe germline mutations of RRAS2 as a new, rare cause of Noonan syndrome. In one study, led by the Institute of Human Genetics of the University Magdeburg, researchers identified in six non-related families autosomal dominant variants in RRAS2 as the underlying cause of Noonan syndrome in their patients. They also describe the predicted effects of the identified mutations as increasing the activity of the MAPK signaling cascade and affecting cell morphology and cytoskeletal rearrangement.