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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.

SUBMITTER: Capri Y 

PROVIDER: S-EPMC6562003 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Capri Yline Y   Flex Elisabetta E   Krumbach Oliver H F OHF   Carpentieri Giovanna G   Cecchetti Serena S   Lißewski Christina C   Rezaei Adariani Soheila S   Schanze Denny D   Brinkmann Julia J   Piard Juliette J   Pantaleoni Francesca F   Lepri Francesca R FR   Goh Elaine Suk-Ying ES   Chong Karen K   Stieglitz Elliot E   Meyer Julia J   Kuechler Alma A   Bramswig Nuria C NC   Sacharow Stephanie S   Strullu Marion M   Vial Yoann Y   Vignal Cédric C   Kensah George G   Cuturilo Goran G   Kazemein Jasemi Neda S NS   Dvorsky Radovan R   Monaghan Kristin G KG   Vincent Lisa M LM   Cavé Hélène H   Verloes Alain A   Ahmadian Mohammad R MR   Tartaglia Marco M   Zenker Martin M  

American journal of human genetics 20190523 6

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 p  ...[more]