Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis
Flex E, Jaiswal M, Pantaleoni F, Martinelli E, Strullu M, Fansa EK, Caye A, De Luca A, Lepri F, Dvorsky R, Pannone L, Paolacci S, Zhang S-C, Fodale V, Bocchinfuso G, Rossi C, Burkitt-Wright EMM, Farrotti A, Stellacci E, Cecchetti S, Ferese R, Bottero L, Castro S, Fenneteau O, Brethon B, Sanchez M, Roberts AE, Yntema HG, Van Der Burgt I, Cianci P, Bondeson ML, Digilio MC, Zampino G, Kerr B, Aoki BK, Loh ML, Palleschi A, Di Schiavi E, Care A, Selicorni A, Dallapiccola B, Cirstea IC, Stella L, Zenker M, Gelb BD, Cave H, Ahmadian MR, Tartaglia M
Human Molecular Genetics 23 (16): 4315-4327. (2014) doi: 10.1093/hmg/ddu148
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 inCaenorhabditis 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.
