RASopathies are group of genetic syndromes cased due to mutation in genes (somatic) in RAS/MAPK pathway. The possible syndromes include Neurofibromatosis type 1 (NF1), Legius syndrome, Noonan syndrome (NS), Costello syndrome, autosomal dominant intellectual disability type five and many others. Commonly the RASopathoes represent developmental malformation syndrome. This article represents the short note about RASopathies and the pathogenetics behind.
RAS/MAPK pathway plays a pivotal role in cancer as well as in development. Genetic mutation in any of the pathway molecule may lead to different RASopathies as discussed above. Ras proteins are guanosine nucleotide-bound GTPases which is activated through multiple mechanisms including growth factors binding to receptor tyrosine kinases (RTK). This binding promotes RTK to auto-phosphorylation and interaction with growth factor receptor-bound protein 2 (GRB2). GRB2 then binds to son of sevenless (SOS) that is recruited to plasma membrane.
SOS is a guanosine nucleotide exchange factors (GEFs) that increase Ras’s GDP exchange rate for GTP. The activated Ras then lead to the activation of Raf (ARAF, BRAF and CRAF). Then a serious of phosphorylated events takes place for MEK and ERK. Finally the ERK1 and ERK2 are the ultimate effectors which functions to modulate downstream molecules.
Pathogenetics in Rasopathies
Ras signals to multiple intracellular pathways and the central pathogenetic denominator for Rasopathies is RAS/MAPK pathway activation. As mentioned before each mutations within this pathay leads to different Rasopathies as the distinct mutations affect the fundamental molecular mechanism of the pathway.
Table: Functional Characterization of genes associated with RASopathies (Follow Reference)
Ras effecter pathways are down regulated or up regulated or sudden aberration due to different mutations generated within the pathway. Functional studies have generated enhanced pathway signalling due to the majority of mutations. Each Rasopathy is unrelated or unique. Upstream of Ras mutation causes aberrant Ras activation like mutation in PTPN11 and RasGAP; whereas downstream mutation of Ras may reflect intolerance for such mutations in development. It is important to decipher the function or aberration caused by the mutations to understand pathogenetic etiology.
Tidylman WE, Rauen KA (2016) Pathogenetics of the RASopathies. Human Molecular Genetics. July 12, 2016.