1. Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome.
- Author
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Capri Y, Flex E, Krumbach OHF, Carpentieri G, Cecchetti S, Lißewski C, Rezaei Adariani S, Schanze D, Brinkmann J, Piard J, Pantaleoni F, Lepri FR, Goh ES, Chong K, Stieglitz E, Meyer J, Kuechler A, Bramswig NC, Sacharow S, Strullu M, Vial Y, Vignal C, Kensah G, Cuturilo G, Kazemein Jasemi NS, Dvorsky R, Monaghan KG, Vincent LM, Cavé H, Verloes A, Ahmadian MR, Tartaglia M, and Zenker M
- Subjects
- Adult, Child, Female, Genetic Association Studies, HEK293 Cells, Humans, Infant, Infant, Newborn, Male, Membrane Proteins chemistry, Membrane Proteins metabolism, Monomeric GTP-Binding Proteins chemistry, Monomeric GTP-Binding Proteins metabolism, Noonan Syndrome pathology, Pedigree, Protein Conformation, Gain of Function Mutation, Guanosine Triphosphate metabolism, Membrane Proteins genetics, Monomeric GTP-Binding Proteins genetics, Noonan Syndrome etiology
- 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., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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