The molecular genetics of RASopathies: An update on novel disease genes and new disorders

Abstract

Enhanced signaling through RAS and the mitogen-associated protein kinase (MAPK) cascade underlies the RASopathies, a family of clinically related disorders affecting development and growth. In RASopathies, increased RAS-MAPK signaling can result from the upregulated activity of various RAS GTPases, enhanced function of proteins positively controlling RAS function or favoring the efficient transmission of RAS signaling to downstream transducers, functional upregulation of RAS effectors belonging to the MAPK cascade, or inefficient signaling switch-off operated by feedback mechanisms acting at different levels. The massive effort in RASopathy gene discovery performed in the last 20 years has identified more than 20 genes implicated in these disorders. It has also facilitated the characterization of several molecular activating mechanisms that had remained unappreciated due to their minor impact in oncogenesis. Here, we provide an overview on the discoveries collected during the last 5 years that have delivered unexpected insights (e.g., Noonan syndrome as a recessive disease) and allowed to profile new RASopathies, novel disease genes and new molecular circuits contributing to the control of RAS-MAPK signaling.

Keywords: LZTR1; MAPK1; MRAS; RAS signaling; RRAS2; SPRED2.

FIGURE 1

RASopathy genes and the role of their encoded proteins in the RAS‐MAPK signaling cascades. (a) Cartoon listing the genes implicated in RASopathies and their year of discovery. Genes requiring further clinical delineation and/or functional validation in the context of the RASopathies are shown in red. Milestones linked to these discoveries are also reported. D and R indicate dominant and recessive, respectively. (b) The RAS‐MAPK signaling cascade. The cartoon shows the signal flow through the pathway (black arrows), together with the proteins positively (blue) and negatively (red) controlling the cascade. Signaling upregulation occurring in RASopathies results from enhanced activity of RAS proteins (i.e., HRAS, KRAS, NRAS, MRAS, RRAS, RRAS2, and RIT1), upstream positive signal transducers and regulators (i.e., SHP2, SOS1, and SOS2), proteins favoring transmission of RAS signaling to downstream transducers (i.e., MRAS, SHOC2, and PPP1CB), and tiers of the MAPK cascade (i.e., BRAF, RAF1, MAP2K1, MAP2K2, and MAPK1). Signaling upregulation also results from inefficient signaling switch‐off operated by multiple feedback mechanisms (i.e., defective/impaired function of CBL, neurofibromin, LZTR1, SPRED1, and SPRED2). P and Ub indicate phosphorylation and ubiquitination, respectively.