Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy

Marialetizia Motta, Lena Sagi-Dain, Oliver H F Krumbach, Andreas Hahn, Amir Peleg, Alina German, Christina Lissewski, Simona Coppola, Francesca Pantaleoni, Luisa Kocherscheid, Franziska Altmüller, Denny Schanze, Thushiha Logeswaran, Soheyla Chahrokh-Zadeh, Anna Munzig, Saeideh Nakhaei-Rad, Hélène Cavé, Mohammad R Ahmadian, Marco Tartaglia, Martin Zenker

Research output: Contribution to journalArticle

Abstract

The RASopathies are a group of genetic syndromes caused by upregulated RAS signaling. Noonan syndrome (NS), the most common entity among the RASopathies, is characterized mainly by short stature, cardiac anomalies and distinctive facial features. Mutations in multiple RAS-MAPK pathway-related genes have been associated with NS and related phenotypes. We describe two unrelated patients presenting with hypertrophic cardiomyopathy (HCM) and dysmorphic features suggestive of NS. One of them died in the neonatal period because of cardiac failure. Targeted sequencing revealed de novo MRAS variants, c.203C > T (p.Thr68Ile) and c.67G > C (p.Gly23Arg) as causative events. MRAS has only recently been related to NS based on the observation of two unrelated affected individuals with de novo variants involving the same codons here found mutated. Gly23 and Thr68 are highly conserved residues, and the corresponding codons are known hotspots for RASopathy-associated mutations in other RAS proteins. Functional analyses documented high level of activation of MRAS mutants due to impaired GTPase activity, which was associated with constitutive plasma membrane targeting, prolonged localization in non-raft microdomains, enhanced binding to PPP1CB and SHOC2 protein, and variably increased MAPK and PI3K-AKT activation. This report provides additional evidence that a narrow spectrum of activating mutations in MRAS represents another rare cause of NS, and that MRAS has to be counted among the RASopathy genes predisposing to HCM. Moreover, our findings further emphasize the relevance of the MRAS-SHOC2-PPP1CB axis in the control of MAPK signaling, and the contribution of both MAPK and PI3K-AKT pathways in MRAS functional upregulation.

Original languageEnglish
JournalHuman Molecular Genetics
DOIs
Publication statusE-pub ahead of print - May 21 2019

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Noonan Syndrome
Hypertrophic Cardiomyopathy
Mutation
Phosphatidylinositol 3-Kinases
Codon
GTP Phosphohydrolases
Genes
Proteins
Up-Regulation
Heart Failure
Cell Membrane
Observation
Phenotype

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Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy. / Motta, Marialetizia; Sagi-Dain, Lena; Krumbach, Oliver H F; Hahn, Andreas; Peleg, Amir; German, Alina; Lissewski, Christina; Coppola, Simona; Pantaleoni, Francesca; Kocherscheid, Luisa; Altmüller, Franziska; Schanze, Denny; Logeswaran, Thushiha; Chahrokh-Zadeh, Soheyla; Munzig, Anna; Nakhaei-Rad, Saeideh; Cavé, Hélène; Ahmadian, Mohammad R; Tartaglia, Marco; Zenker, Martin.

In: Human Molecular Genetics, 21.05.2019.

Research output: Contribution to journalArticle

Motta, M, Sagi-Dain, L, Krumbach, OHF, Hahn, A, Peleg, A, German, A, Lissewski, C, Coppola, S, Pantaleoni, F, Kocherscheid, L, Altmüller, F, Schanze, D, Logeswaran, T, Chahrokh-Zadeh, S, Munzig, A, Nakhaei-Rad, S, Cavé, H, Ahmadian, MR, Tartaglia, M & Zenker, M 2019, 'Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy', Human Molecular Genetics. https://doi.org/10.1093/hmg/ddz108
Motta, Marialetizia ; Sagi-Dain, Lena ; Krumbach, Oliver H F ; Hahn, Andreas ; Peleg, Amir ; German, Alina ; Lissewski, Christina ; Coppola, Simona ; Pantaleoni, Francesca ; Kocherscheid, Luisa ; Altmüller, Franziska ; Schanze, Denny ; Logeswaran, Thushiha ; Chahrokh-Zadeh, Soheyla ; Munzig, Anna ; Nakhaei-Rad, Saeideh ; Cavé, Hélène ; Ahmadian, Mohammad R ; Tartaglia, Marco ; Zenker, Martin. / Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy. In: Human Molecular Genetics. 2019.
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abstract = "The RASopathies are a group of genetic syndromes caused by upregulated RAS signaling. Noonan syndrome (NS), the most common entity among the RASopathies, is characterized mainly by short stature, cardiac anomalies and distinctive facial features. Mutations in multiple RAS-MAPK pathway-related genes have been associated with NS and related phenotypes. We describe two unrelated patients presenting with hypertrophic cardiomyopathy (HCM) and dysmorphic features suggestive of NS. One of them died in the neonatal period because of cardiac failure. Targeted sequencing revealed de novo MRAS variants, c.203C > T (p.Thr68Ile) and c.67G > C (p.Gly23Arg) as causative events. MRAS has only recently been related to NS based on the observation of two unrelated affected individuals with de novo variants involving the same codons here found mutated. Gly23 and Thr68 are highly conserved residues, and the corresponding codons are known hotspots for RASopathy-associated mutations in other RAS proteins. Functional analyses documented high level of activation of MRAS mutants due to impaired GTPase activity, which was associated with constitutive plasma membrane targeting, prolonged localization in non-raft microdomains, enhanced binding to PPP1CB and SHOC2 protein, and variably increased MAPK and PI3K-AKT activation. This report provides additional evidence that a narrow spectrum of activating mutations in MRAS represents another rare cause of NS, and that MRAS has to be counted among the RASopathy genes predisposing to HCM. Moreover, our findings further emphasize the relevance of the MRAS-SHOC2-PPP1CB axis in the control of MAPK signaling, and the contribution of both MAPK and PI3K-AKT pathways in MRAS functional upregulation.",
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T1 - Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy

AU - Motta, Marialetizia

AU - Sagi-Dain, Lena

AU - Krumbach, Oliver H F

AU - Hahn, Andreas

AU - Peleg, Amir

AU - German, Alina

AU - Lissewski, Christina

AU - Coppola, Simona

AU - Pantaleoni, Francesca

AU - Kocherscheid, Luisa

AU - Altmüller, Franziska

AU - Schanze, Denny

AU - Logeswaran, Thushiha

AU - Chahrokh-Zadeh, Soheyla

AU - Munzig, Anna

AU - Nakhaei-Rad, Saeideh

AU - Cavé, Hélène

AU - Ahmadian, Mohammad R

AU - Tartaglia, Marco

AU - Zenker, Martin

N1 - © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PY - 2019/5/21

Y1 - 2019/5/21

N2 - The RASopathies are a group of genetic syndromes caused by upregulated RAS signaling. Noonan syndrome (NS), the most common entity among the RASopathies, is characterized mainly by short stature, cardiac anomalies and distinctive facial features. Mutations in multiple RAS-MAPK pathway-related genes have been associated with NS and related phenotypes. We describe two unrelated patients presenting with hypertrophic cardiomyopathy (HCM) and dysmorphic features suggestive of NS. One of them died in the neonatal period because of cardiac failure. Targeted sequencing revealed de novo MRAS variants, c.203C > T (p.Thr68Ile) and c.67G > C (p.Gly23Arg) as causative events. MRAS has only recently been related to NS based on the observation of two unrelated affected individuals with de novo variants involving the same codons here found mutated. Gly23 and Thr68 are highly conserved residues, and the corresponding codons are known hotspots for RASopathy-associated mutations in other RAS proteins. Functional analyses documented high level of activation of MRAS mutants due to impaired GTPase activity, which was associated with constitutive plasma membrane targeting, prolonged localization in non-raft microdomains, enhanced binding to PPP1CB and SHOC2 protein, and variably increased MAPK and PI3K-AKT activation. This report provides additional evidence that a narrow spectrum of activating mutations in MRAS represents another rare cause of NS, and that MRAS has to be counted among the RASopathy genes predisposing to HCM. Moreover, our findings further emphasize the relevance of the MRAS-SHOC2-PPP1CB axis in the control of MAPK signaling, and the contribution of both MAPK and PI3K-AKT pathways in MRAS functional upregulation.

AB - The RASopathies are a group of genetic syndromes caused by upregulated RAS signaling. Noonan syndrome (NS), the most common entity among the RASopathies, is characterized mainly by short stature, cardiac anomalies and distinctive facial features. Mutations in multiple RAS-MAPK pathway-related genes have been associated with NS and related phenotypes. We describe two unrelated patients presenting with hypertrophic cardiomyopathy (HCM) and dysmorphic features suggestive of NS. One of them died in the neonatal period because of cardiac failure. Targeted sequencing revealed de novo MRAS variants, c.203C > T (p.Thr68Ile) and c.67G > C (p.Gly23Arg) as causative events. MRAS has only recently been related to NS based on the observation of two unrelated affected individuals with de novo variants involving the same codons here found mutated. Gly23 and Thr68 are highly conserved residues, and the corresponding codons are known hotspots for RASopathy-associated mutations in other RAS proteins. Functional analyses documented high level of activation of MRAS mutants due to impaired GTPase activity, which was associated with constitutive plasma membrane targeting, prolonged localization in non-raft microdomains, enhanced binding to PPP1CB and SHOC2 protein, and variably increased MAPK and PI3K-AKT activation. This report provides additional evidence that a narrow spectrum of activating mutations in MRAS represents another rare cause of NS, and that MRAS has to be counted among the RASopathy genes predisposing to HCM. Moreover, our findings further emphasize the relevance of the MRAS-SHOC2-PPP1CB axis in the control of MAPK signaling, and the contribution of both MAPK and PI3K-AKT pathways in MRAS functional upregulation.

U2 - 10.1093/hmg/ddz108

DO - 10.1093/hmg/ddz108

M3 - Article

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

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