TY - JOUR
T1 - Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis
AU - Flex, Elisabetta
AU - Jaiswal, Mamta
AU - Pantaleoni, Francesca
AU - Martinelli, Simone
AU - Strullu, Marion
AU - Fansa, Eyad K.
AU - Caye, Aurélie
AU - De Luca, Alessandro
AU - Lepri, Francesca
AU - Dvorsky, Radovan
AU - Pannone, Luca
AU - Paolacci, Stefano
AU - Zhang, Si Cai
AU - Fodale, Valentina
AU - Bocchinfuso, Gianfranco
AU - Rossi, Cesare
AU - Burkitt-Wright, Emma M.M.
AU - Farrotti, Andrea
AU - Stellacci, Emilia
AU - Cecchetti, Serena
AU - Ferese, Rosangela
AU - Bottero, Lisabianca
AU - Castro, Silvana
AU - Fenneteau, Odile
AU - Brethon, Benoît
AU - Sanchez, Massimo
AU - Roberts, Amy E.
AU - Yntema, Helger G.
AU - Van Der Burgt, Ineke
AU - Cianci, Paola
AU - Bondeson, Marie Louise
AU - Digilio, Maria Cristina
AU - Zampino, Giuseppe
AU - Kerr, Bronwyn
AU - Aoki, Yoko K.
AU - Loh, Mignon L.
AU - Palleschi, Antonio
AU - Di Schiavi, Elia
AU - Caré, Alessandra
AU - Selicorni, Angelo
AU - Dallapiccola, Bruno
AU - Cirstea, Ion C.
AU - Stella, Lorenzo
AU - Zenker, Martin
AU - Gelb, Bruce D.
AU - Cavé, Héléne
AU - Ahmadian, Mohammad R.
AU - Tartaglia, Marco
N1 - Funding Information:
We are grateful to the participating patients and their families. We thank Serenella Venanzi (Istituto Superiore di Sanità, Rome, Italy), Michela Bonaguro (Policlinico S.Orsola-Malpighi, Bologna, Italy), Federica Consoli (Istituto Mendel, Rome, Italy) and Cédric Vignal and Sabrina Pereira (Hôpital Robert Debré, Paris, France) for skilful technical assistance, and the Open Laboratory (IGB-CNR, Naples, Italy) for experimental support. We also thank Paolo Bazzicalupo (IGB-CNR) for critical reading of the manuscript, paediatricians from the Société Franc¸aise des Cancers de l’Enfant (SFCE) for providing biological material from their patients and CINECA for computational resources. Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center (University of Minnesota, Minneapolis, MN, USA) funded by the NIH Office of Research Infrastructure Programs (P40OD010440).
Funding Information:
This work was supported by grants from the ERA-Net for research programmes on rare diseases 2009 (NSEuroNet to M.Z., H.C., M.R.A. and M.T.), Telethon-Italy (GGP10020 and GGP13107 to M.T.), AIRC (IG 13360 to M.T.), NGFNplus program of the German Ministry of Science and Education (01GS08100 to M.R.A.), German Research Foundation through the Collaborative Research Center 974 (Communication and Systems Relevance during Liver Injury and Regeneration to M.R.A.) and NIH (HL071207 to B.D.G.). F.P. was recipient of a research fellowship from ‘Associazione Italiana Sindromi di Costello e cardiofaciocutanea’. Funding to pay the Open Access publication charges for this article was provided by Telethon-Italy.
PY - 2014/8
Y1 - 2014/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84904763680&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904763680&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddu148
DO - 10.1093/hmg/ddu148
M3 - Article
C2 - 24705357
AN - SCOPUS:84904763680
SN - 0964-6906
VL - 23
SP - 4315
EP - 4327
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 16
M1 - ddu148
ER -
