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Am J Hum Genet. 2019 Jun 6;104(6):1223-1232. doi: 10.1016/j.ajhg.2019.04.013. Epub 2019 May 23.

Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome.

Author information

1
Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP) Hôpital Robert Debré, 75019 Paris, France.
2
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
3
Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich Heine University, 40225 Düsseldorf, Germany.
4
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
5
Microscopy Area, Core Facilities, Istituto Superiore di Sanità, 00161 Rome, Italy.
6
Institute of Human Genetics, University Hospital Magdeburg, 39120 Magdeburg, Germany.
7
Human Genetic Center - CHU St Jacques, 25000 Besancon, France.
8
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
9
Laboratory Medicine and Genetics, Trillium Health Partners, Mississauga, ON L5M 2N1, Canada.
10
Department of Obstetrics and Gynecology, The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, ON M5G 1Z5, Canada.
11
Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94107, USA.
12
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45147 Essen, Germany.
13
Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
14
Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP) Hôpital Robert Debré, 75019 Paris, France; INSERM UMR 1131, Institut de Recherche Saint-Louis, Université de Paris, 75010 Paris, France.
15
Department of Thoracic and Cardiovascular Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany.
16
Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; University Children's Hospital, 11000 Belgrade, Serbia.
17
GeneDx, Gaithersburg, MD 20877, USA.
18
GeneDx, Gaithersburg, MD 20877, USA; Center for Cancer of Blood Disorders, Children's National Health System, Washington, DC 20010, USA.
19
Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP) Hôpital Robert Debré, 75019 Paris, France; INSERM UMR 1141 - Université de Paris, 75019 Paris, France.
20
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address: marco.tartaglia@opbg.net.
21
Institute of Human Genetics, University Hospital Magdeburg, 39120 Magdeburg, Germany. Electronic address: martin.zenker@med.ovgu.de.

Abstract

Aberrant signaling through pathways controlling cell response to extracellular stimuli constitutes a central theme in disorders affecting development. Signaling through RAS and the MAPK cascade controls a variety of cell decisions in response to cytokines, hormones, and growth factors, and its upregulation causes Noonan syndrome (NS), a developmental disorder whose major features include a distinctive facies, a wide spectrum of cardiac defects, short stature, variable cognitive impairment, and predisposition to malignancies. NS is genetically heterogeneous, and mutations in more than ten genes have been reported to underlie this disorder. Despite the large number of genes implicated, about 10%-20% of affected individuals with a clinical diagnosis of NS do not have mutations in known RASopathy-associated genes, indicating that additional unidentified genes contribute to the disease, when mutated. By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families. We show that the NS-causing RRAS2 variants affect highly conserved residues localized around the nucleotide binding pocket of the GTPase and are predicted to variably affect diverse aspects of RRAS2 biochemical behavior, including nucleotide binding, GTP hydrolysis, and interaction with effectors. Additionally, all pathogenic variants increase activation of the MAPK cascade and variably impact cell morphology and cytoskeletal rearrangement. Finally, we provide a characterization of the clinical phenotype associated with RRAS2 mutations.

KEYWORDS:

MAPK; Noonan syndrome; RAS; RASopathies; RRAS2

PMID:
31130282
PMCID:
PMC6562003
DOI:
10.1016/j.ajhg.2019.04.013
[Indexed for MEDLINE]
Free PMC Article

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