Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome
| Autor: | Francesca Romana Lepri, Martin Zenker, Christina Lißewski, Alma Kuechler, Lisa M. Vincent, Elisabetta Flex, Elaine Suk-Ying Goh, Francesca Pantaleoni, Serena Cecchetti, Yline Capri, Kristin G. Monaghan, Giovanna Carpentieri, Mohammad Reza Ahmadian, Marion Strullu, Goran Cuturilo, Hélène Cavé, Cédric Vignal, Alain Verloes, Nuria C. Bramswig, Julia Meyer, Neda S. Kazemein Jasemi, Elliot Stieglitz, Denny Schanze, Oliver H.F. Krumbach, Karen Chong, Radovan Dvorsky, Soheila Rezaei Adariani, Stephanie Sacharow, Marco Tartaglia, Julia Brinkmann, Yoann Vial, Juliette Piard, G. Kensah |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine MAPK/ERK pathway Protein Conformation Medizin GTPase 030105 genetics & heredity MAPK cascade Medical and Health Sciences Noonan syndrome 2.1 Biological and endogenous factors Aetiology Child Genetics (clinical) Exome sequencing Pediatric Genetics & Heredity Genetics Noonan Syndrome Biological Sciences Pedigree Gain of Function Mutation Female Guanosine Triphosphate RRAS2 Adult Intellectual and Developmental Disabilities (IDD) Biology 03 medical and health sciences Downregulation and upregulation Report medicine Humans RASopathies Gene Genetic Association Studies Monomeric GTP-Binding Proteins Genetic heterogeneity Infant Newborn Infant Membrane Proteins Newborn medicine.disease MAPK Brain Disorders HEK293 Cells 030104 developmental biology Congenital Structural Anomalies RAS |
| Zdroj: | American journal of human genetics, vol 104, iss 6 |
| ISSN: | 0002-9297 |
| Popis: | 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 cellmorphology and cytoskeletal rearrangement. Finally, we provide a characterization of the clinical phenotype associated with RRAS2 mutations. |
| Databáze: | OpenAIRE |
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