Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis

Abstract

RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2S2G mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease.

Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations

“…Mutations at that RRAS G39 promote enhanced serum-dependent MEK, ERK, and AKT phosphorylation in vitro. 30 We identified mutations in several genes (eg, PAK3, USP6, ABCF1, STK39) that were uncommon but may confer important effects within individual PTNFLs. Further study is needed to determine the contribution of these mutations within cases of PTNFL.…”

K-Ras V14I recapitulates Noonan syndrome in mice

“…Less frequently, these patients develop severe MPD, juvenile myelomonocytic leukemia (JMML), or other forms of leukemia (2,5). NS is inherited in an autosomal dominant manner and results from germ-line mutations in at least 11 different genes including Protein Tyrosine Phosphatase Non-Receptor type 11 (PTPN11), Son of Sevenless homolog 1 (SOS1), KRAS, NRAS, RAF1, BRAF, MEK1, SHOC2, CBL, RIT1, and RRAS, most of which are involved in mediating RAS signaling (3,(6)(7)(8). Among these loci, PTPN11 is the most frequently mutated, in about 50% of NS patients.…”

Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia

“…Indeed, we have recently shown that RRAS, another RAS-like GTPase, is mutated in rare cases of NS and in some cases of JMML. 9 Similar to classic Ras and R-Ras, Rit proteins have been shown to display oncogenic properties, and GTPasedeficient variants cause growth transformation in NIH 3T3 mouse fibroblasts. 30 The expression of wild-type or oncogenic RIT1 in PC6 cells induces in most cases both the phosphorylation of ERK via MEK activation and a robust activation of PI3K/AKT signaling.…”