Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome

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 StrulluYoann 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

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)1223-1232
Number of pages10
JournalAmerican Journal of Human Genetics
Volume104
Issue number6
DOIs
Publication statusPublished - Jun 6 2019

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Noonan Syndrome
Mutation
Genes
Nucleotides
Exome
GTP Phosphohydrolases
Guanosine Triphosphate
Intercellular Signaling Peptides and Proteins
Hydrolysis
Up-Regulation
Hormones
Cytokines
Phenotype
Neoplasms

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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 journalArticle

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-Y, 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 & Zenker, M 2019, 'Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome', American Journal of Human Genetics, vol. 104, no. 6, pp. 1223-1232. https://doi.org/10.1016/j.ajhg.2019.04.013
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. / Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome. In: American Journal of Human Genetics. 2019 ; Vol. 104, No. 6. pp. 1223-1232.
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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.",
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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

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