Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis.
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 SHOC2(S2G) 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.
Dipartimento di Ematologia, Oncologia e Medicina Molecolare and.
Elisabetta
E
Flex
Institut für Biochemie und Molekularbiologie II, Medizinische Fakultät der Heinrich-Heine Universitat, Düsseldorf 40225, Germany.
Mamta
M
Jaiswal
Dipartimento di Ematologia, Oncologia e Medicina Molecolare and.
Francesca
F
Pantaleoni
Dipartimento di Ematologia, Oncologia e Medicina Molecolare and.
Simone
S
Martinelli
Genetics Department, INSERM UMR_S940, Institut Universitaire D'Hématologie (IUH), Université Paris-Diderot Sorbonne-Paris-Cité, Paris 75010, France.
Marion
M
Strullu
Institut für Biochemie und Molekularbiologie II, Medizinische Fakultät der Heinrich-Heine Universitat, Düsseldorf 40225, Germany.
Eyad K
EK
Fansa
Genetics Department, INSERM UMR_S940, Institut Universitaire D'Hématologie (IUH), Université Paris-Diderot Sorbonne-Paris-Cité, Paris 75010, France.
Aurélie
A
Caye
Laboratorio Mendel, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo Della Sofferenza, Rome 00198, Italy.
Alessandro
A
De Luca
Ospedale Pediatrico 'Bambino Gesù', Rome 00165, Italy.
Francesca
F
Lepri
Institut für Biochemie und Molekularbiologie II, Medizinische Fakultät der Heinrich-Heine Universitat, Düsseldorf 40225, Germany.
Radovan
R
Dvorsky
Dipartimento di Ematologia, Oncologia e Medicina Molecolare and.
Luca
L
Pannone
Dipartimento di Ematologia, Oncologia e Medicina Molecolare and.
Stefano
S
Paolacci
Institut für Biochemie und Molekularbiologie II, Medizinische Fakultät der Heinrich-Heine Universitat, Düsseldorf 40225, Germany.
Si-Cai
SC
Zhang
Dipartimento di Ematologia, Oncologia e Medicina Molecolare and.
Valentina
V
Fodale
Dipartimento di Scienze e Tecnologie Chimiche, Università 'Tor Vergata', Rome 00133, Italy.
Gianfranco
G
Bocchinfuso
UO Genetica Medica, Policlinico S.Orsola-Malpighi, Bologna 40138, Italy.
Cesare
C
Rossi
Genetic Medicine, Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UK.
Emma M M
EM
Burkitt-Wright
Dipartimento di Scienze e Tecnologie Chimiche, Università 'Tor Vergata', Rome 00133, Italy.
Andrea
A
Farrotti
Dipartimento di Ematologia, Oncologia e Medicina Molecolare and.
Emilia
E
Stellacci
Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Rome 00161, Italy.
Serena
S
Cecchetti
Laboratorio Mendel, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo Della Sofferenza, Rome 00198, Italy.
Rosangela
R
Ferese
Dipartimento di Ematologia, Oncologia e Medicina Molecolare and.
Lisabianca
L
Bottero
Istituto di Genetica e Biofisica 'A. Buzzati Traverso', Consiglio Nazionale Delle Ricerche, Naples 80131, Italy.
Silvana
S
Castro
Biological Hematology Department and.
Odile
O
Fenneteau
Pediatric Hematology Department, Robert Debré Hospital, Paris 75019, France.
Benoît
B
Brethon
Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Rome 00161, Italy.
Massimo
M
Sanchez
Department of Cardiology and Division of Genetics, and Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Amy E
AE
Roberts
Department of Human Genetics, Radboud University Medical Centre, and Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen 6500, The Netherlands.
Helger G
HG
Yntema
Department of Human Genetics, Radboud University Medical Centre, and Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen 6500, The Netherlands.
Ineke
I
Van Der Burgt
Genetica Clinica Pediatrica, Clinica Pediatrica Università Milano Bicocca, Fondazione MBBM, A.O. S. Gerardo, Monza 20900, Italy.
Paola
P
Cianci
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 75237, Sweden.
Marie-Louise
ML
Bondeson
Ospedale Pediatrico 'Bambino Gesù', Rome 00165, Italy.
Maria
M
Cristina Digilio
Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome 00168, Italy.
Giuseppe
G
Zampino
Genetic Medicine, Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UK.
Bronwyn
B
Kerr
Department of Medical Genetics, Tohoku University School of Medicine, Sendai 980-8574, Japan.
Yoko
Y
Aoki
Department of Pediatrics, Benioff Children's Hospital, University of California School of Medicine, and the Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, 94143, USA.
Mignon L
ML
Loh
Dipartimento di Scienze e Tecnologie Chimiche, Università 'Tor Vergata', Rome 00133, Italy.
Antonio
A
Palleschi
Istituto di Genetica e Biofisica 'A. Buzzati Traverso', Consiglio Nazionale Delle Ricerche, Naples 80131, Italy.
Elia
E
Di Schiavi
Dipartimento di Ematologia, Oncologia e Medicina Molecolare and.
Alessandra
A
Carè
Genetica Clinica Pediatrica, Clinica Pediatrica Università Milano Bicocca, Fondazione MBBM, A.O. S. Gerardo, Monza 20900, Italy.
Angelo
A
Selicorni
Ospedale Pediatrico 'Bambino Gesù', Rome 00165, Italy.
Bruno
B
Dallapiccola
Institut für Biochemie und Molekularbiologie II, Medizinische Fakultät der Heinrich-Heine Universitat, Düsseldorf 40225, Germany, Leibniz Institute for Age Research, Jena 07745, Germany.
Ion C
IC
Cirstea
Dipartimento di Scienze e Tecnologie Chimiche, Università 'Tor Vergata', Rome 00133, Italy.
Lorenzo
L
Stella
Institute of Human Genetics, University Hospital of Magdeburg, Otto-von-Guericke-University, Magdeburg 39120, Germany.
Martin
M
Zenker
Department of Pediatrics and Department of Genetics and Department of Genomic Sciences, Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Bruce D
BD
Gelb
Genetics Department, INSERM UMR_S940, Institut Universitaire D'Hématologie (IUH), Université Paris-Diderot Sorbonne-Paris-Cité, Paris 75010, France.
Hélène
H
Cavé
Institut für Biochemie und Molekularbiologie II, Medizinische Fakultät der Heinrich-Heine Universitat, Düsseldorf 40225, Germany.
Mohammad R
MR
Ahmadian
Dipartimento di Ematologia, Oncologia e Medicina Molecolare and marco.tartaglia@iss.it.
Marco
M
Tartaglia
D000818:Animals; D017173:Caenorhabditis elegans; D063646:Carcinogenesis / Q000235:genetics*; D015331:Cohort Studies; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D009154:Mutation / Q000502:physiology*; D009634:Noonan Syndrome / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D018631:ras Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; C085929:RRAS protein, human; D018631:ras Proteins