Understanding the RAS in RASopathies

RASopathies are a collection of conditions caused by hyperactivation of the mitogen-activated protein kinase (MAPK) pathway. Mutations in RAS genes themselves occur in Noonan Syndrome, Cardio-facio-cutaneous syndrome, and Costello syndrome. These mutations are considered weak alleles relative to mutations that cause cancer. RAS-related genes, RRAS, RRAS2, MRAS, and RIT1 are also activated by mutation: these proteins do not activate RAF kinase directly in normal cells, but mutant forms gain the capacity to activate RAF kinase sufficiently to cause disease. Loss-of-function mutations occur in RASGAPs, and gain-of-function mutations occur in RASGEFs. Genes involved in upregulating RAS signaling indirectly, such as SHOC2, PP1C, LZTR1, and 14-3-3 also cause RASopathies. Analysis of structural and biochemical properties of these mutant proteins provides valuable insights into their regulation and function and suggests therapeutic opportunities for RASopathies and other conditions in which they are involved.