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

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.

• Authors: Yline Capri, Elisabetta Flex, Oliver H F Krumbach, Giovanna Carpentieri, Serena Cecchetti, Christina Lißewski, Soheila Rezaei Adariani, Denny Schanze, Julia Brinkmann, Juliette Piard, Francesca Pantaleoni, Francesca R Lepri, Elaine Suk-Ying Goh, Karen Chong, Elliot Stieglitz, Julia Meyer, Alma Kuechler, Nuria C Bramswig, Stephanie Sacharow, Marion Strullu, Yoann Vial, Cédric Vignal, George Kensah, Goran Cuturilo, Neda S Kazemein Jasemi, Radovan Dvorsky, Kristin G Monaghan, Lisa M Vincent, Hélène Cavé, Alain Verloes, Mohammad R Ahmadian, Marco Tartaglia, Martin Zenker
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 104 Issue 6 Pg. 1223-1232 (06 06 2019) ISSN: 1537-6605 [Electronic] United States
• PMID: 31130282 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Membrane Proteins
• Guanosine Triphosphate
• RRAS2 protein, human
• Monomeric GTP-Binding Proteins

Topics

• Adult
• Child
• Female
• Gain of Function Mutation
• Genetic Association Studies
• Guanosine Triphosphate (metabolism)
• HEK293 Cells
• Humans
• Infant
• Infant, Newborn
• Male
• Membrane Proteins (chemistry, genetics, metabolism)
• Monomeric GTP-Binding Proteins (chemistry, genetics, metabolism)
• Noonan Syndrome (etiology, pathology)
• Pedigree
• Protein Conformation