Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis
Open Access
- 4 April 2014
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 23 (16), 4315-4327
- https://doi.org/10.1093/hmg/ddu148
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.Keywords
This publication has 65 references indexed in Scilit:
- RAS oncogenes: weaving a tumorigenic webNature Reviews Cancer, 2011
- The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensationTrends in Biochemical Sciences, 2011
- Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromesAmerican Journal Of Medical Genetics Part C-Seminars In Medical Genetics, 2011
- Noonan syndrome and clinically related disordersBest Practice & Research Clinical Endocrinology & Metabolism, 2011
- Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disordersHuman Mutation, 2010
- Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hairNature Genetics, 2009
- Mapping the Nucleotide and Isoform-Dependent Structural and Dynamical Features of Ras ProteinsStructure, 2008
- Germline mutations in HRAS proto-oncogene cause Costello syndromeNature Genetics, 2005
- SWISS‐MODEL and the Swiss‐Pdb Viewer: An environment for comparative protein modelingElectrophoresis, 1997
- Molecular dynamics with coupling to an external bathThe Journal of Chemical Physics, 1984