Gene

Kinase

MAPK/ERK pathway

Cell biology

GTPase

Biology

Mutation

Signal transduction

Anti-apoptotic Ras signalling cascade

Biochemistry

Genetics

Noonan syndrome

GTP'

Small GTPase

Enzyme

Effector

KRAS

Costello syndrome

Carcinogenesis

Ras superfamily

American Journal of Medical Genetics Part C Seminars in Medical Genetics

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.

The molecular genetics of <scp>RASopathies</scp>: An update on novel disease genes and new disorders

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