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

Elisabetta Flex, Mamta Jaiswal, Francesca Pantaleoni, Simone Martinelli, Marion Strullu, Eyad K. Fansa, Aurélie Caye, Alessandro De Luca, Francesca Lepri, Radovan Dvorsky, Luca Pannone, Stefano Paolacci, Si Cai Zhang, Valentina Fodale, Gianfranco Bocchinfuso, Cesare Rossi, Emma M.M. Burkitt-Wright, Andrea Farrotti, Emilia Stellacci, Serena CecchettiRosangela Ferese, Lisabianca Bottero, Silvana Castro, Odile Fenneteau, Benoît Brethon, Massimo Sanchez, Amy E. Roberts, Helger G. Yntema, Ineke Van Der Burgt, Paola Cianci, Marie Louise Bondeson, Maria Cristina Digilio, Giuseppe Zampino, Bronwyn Kerr, Yoko K. Aoki, Mignon L. Loh, Antonio Palleschi, Elia Di Schiavi, Alessandra Caré, Angelo Selicorni, Bruno Dallapiccola, Ion C. Cirstea, Lorenzo Stella, Martin Zenker, Bruce D. Gelb, Héléne Cavé, Mohammad R. Ahmadian, Marco Tartaglia

研究成果: Article査読

79 被引用数 (Scopus)


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 identifiedmutations 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.

ジャーナルHuman molecular genetics
出版ステータスPublished - 2014 8

ASJC Scopus subject areas

  • 分子生物学
  • 遺伝学
  • 遺伝学(臨床)


「Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。