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.
| Original language | English |
|---|---|
| Pages (from-to) | 1223-1232 |
| Number of pages | 10 |
| Journal | American Journal of Human Genetics |
| Volume | 104 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 6 2019 |
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Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome. / Capri, Yline; Flex, Elisabetta; Krumbach, Oliver H F; Carpentieri, Giovanna; Cecchetti, Serena; Lißewski, Christina; Rezaei Adariani, Soheila; Schanze, Denny; Brinkmann, Julia; Piard, Juliette; Pantaleoni, Francesca; Lepri, Francesca R; Goh, Elaine Suk-Ying; Chong, Karen; Stieglitz, Elliot; Meyer, Julia; Kuechler, Alma; Bramswig, Nuria C; Sacharow, Stephanie; Strullu, Marion; Vial, Yoann; Vignal, Cédric; Kensah, George; Cuturilo, Goran; Kazemein Jasemi, Neda S; Dvorsky, Radovan; Monaghan, Kristin G; Vincent, Lisa M; Cavé, Hélène; Verloes, Alain; Ahmadian, Mohammad R; Tartaglia, Marco; Zenker, Martin.
In: American Journal of Human Genetics, Vol. 104, No. 6, 06.06.2019, p. 1223-1232.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome
AU - Capri, Yline
AU - Flex, Elisabetta
AU - Krumbach, Oliver H F
AU - Carpentieri, Giovanna
AU - Cecchetti, Serena
AU - Lißewski, Christina
AU - Rezaei Adariani, Soheila
AU - Schanze, Denny
AU - Brinkmann, Julia
AU - Piard, Juliette
AU - Pantaleoni, Francesca
AU - Lepri, Francesca R
AU - Goh, Elaine Suk-Ying
AU - Chong, Karen
AU - Stieglitz, Elliot
AU - Meyer, Julia
AU - Kuechler, Alma
AU - Bramswig, Nuria C
AU - Sacharow, Stephanie
AU - Strullu, Marion
AU - Vial, Yoann
AU - Vignal, Cédric
AU - Kensah, George
AU - Cuturilo, Goran
AU - Kazemein Jasemi, Neda S
AU - Dvorsky, Radovan
AU - Monaghan, Kristin G
AU - Vincent, Lisa M
AU - Cavé, Hélène
AU - Verloes, Alain
AU - Ahmadian, Mohammad R
AU - Tartaglia, Marco
AU - Zenker, Martin
N1 - Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
PY - 2019/6/6
Y1 - 2019/6/6
N2 - 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.
AB - 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.
U2 - 10.1016/j.ajhg.2019.04.013
DO - 10.1016/j.ajhg.2019.04.013
M3 - Article
C2 - 31130282
VL - 104
SP - 1223
EP - 1232
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 6
ER -