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Hum Mol Genet. 2014 Aug 15;23(16):4315-27. doi: 10.1093/hmg/ddu148. Epub 2014 Apr 4.

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

Author information

1
Dipartimento di Ematologia, Oncologia e Medicina Molecolare and.
2
Institut für Biochemie und Molekularbiologie II, Medizinische Fakultät der Heinrich-Heine Universitat, Düsseldorf 40225, Germany.
3
Genetics Department, INSERM UMR_S940, Institut Universitaire D'Hématologie (IUH), Université Paris-Diderot Sorbonne-Paris-Cité, Paris 75010, France.
4
Laboratorio Mendel, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo Della Sofferenza, Rome 00198, Italy.
5
Ospedale Pediatrico 'Bambino Gesù', Rome 00165, Italy.
6
Dipartimento di Scienze e Tecnologie Chimiche, Università 'Tor Vergata', Rome 00133, Italy.
7
UO Genetica Medica, Policlinico S.Orsola-Malpighi, Bologna 40138, Italy.
8
Genetic Medicine, Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UK.
9
Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Rome 00161, Italy.
10
Istituto di Genetica e Biofisica 'A. Buzzati Traverso', Consiglio Nazionale Delle Ricerche, Naples 80131, Italy.
11
Biological Hematology Department and.
12
Pediatric Hematology Department, Robert Debré Hospital, Paris 75019, France.
13
Department of Cardiology and Division of Genetics, and Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
14
Department of Human Genetics, Radboud University Medical Centre, and Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen 6500, The Netherlands.
15
Genetica Clinica Pediatrica, Clinica Pediatrica Università Milano Bicocca, Fondazione MBBM, A.O. S. Gerardo, Monza 20900, Italy.
16
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 75237, Sweden.
17
Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome 00168, Italy.
18
Department of Medical Genetics, Tohoku University School of Medicine, Sendai 980-8574, Japan.
19
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.
20
Institut für Biochemie und Molekularbiologie II, Medizinische Fakultät der Heinrich-Heine Universitat, Düsseldorf 40225, Germany, Leibniz Institute for Age Research, Jena 07745, Germany.
21
Institute of Human Genetics, University Hospital of Magdeburg, Otto-von-Guericke-University, Magdeburg 39120, Germany.
22
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.
23
Dipartimento di Ematologia, Oncologia e Medicina Molecolare and marco.tartaglia@iss.it.

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 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.

PMID:
24705357
PMCID:
PMC4103678
DOI:
10.1093/hmg/ddu148
[Indexed for MEDLINE]
Free PMC Article
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