Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome.
MAPK
Noonan syndrome
RAS
RASopathies
RRAS2
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
06 06 2019
06 06 2019
Historique:
received:
06
03
2019
accepted:
18
04
2019
pubmed:
28
5
2019
medline:
12
3
2020
entrez:
28
5
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31130282
pii: S0002-9297(19)30161-2
doi: 10.1016/j.ajhg.2019.04.013
pmc: PMC6562003
pii:
doi:
Substances chimiques
Membrane Proteins
0
Guanosine Triphosphate
86-01-1
RRAS2 protein, human
EC 3.6.1
Monomeric GTP-Binding Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1223-1232Informations de copyright
Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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