Human Molecular Genetics, ( ISI ), Volume (29), No (11), Year (2019-5) , Pages (1772-1783)

Title : ( Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy )

Authors: Marialetizia Motta , Lena Sagi-Dain , Oliver H. F. Krumbach , Andreas Hahn , Amir Peleg , Alina German , Christina Lissewski , Simona Coppola , Francesca Pantaleoni , Luisa Kocherscheid , Franziska Altmuller , Denny Schanze , Thushiha Logeswaran , Soheyla Chahrokh-Zadeh , Anna Munzig , Saeideh Nakhaeirad , Helene Cave , Mohammad R. Ahmadian , Marco Tartaglia , Martin Zenker ,

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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.

Keywords

, Noonan syndrome, RASopathies, RAS signaling, RAS
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@article{paperid:1077925,
author = {Marialetizia Motta and Lena Sagi-Dain and Oliver H. F. Krumbach and Andreas Hahn and Amir Peleg and Alina German and Christina Lissewski and Simona Coppola and Francesca Pantaleoni and Luisa Kocherscheid and Franziska Altmuller and Denny Schanze and Thushiha Logeswaran and Soheyla Chahrokh-Zadeh and Anna Munzig and Nakhaeirad, Saeideh and Helene Cave and Mohammad R. Ahmadian and Marco Tartaglia and Martin Zenker},
title = {Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy},
journal = {Human Molecular Genetics},
year = {2019},
volume = {29},
number = {11},
month = {May},
issn = {0964-6906},
pages = {1772--1783},
numpages = {11},
keywords = {Noonan syndrome; RASopathies; RAS signaling; RAS},
}

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%0 Journal Article
%T Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy
%A Marialetizia Motta
%A Lena Sagi-Dain
%A Oliver H. F. Krumbach
%A Andreas Hahn
%A Amir Peleg
%A Alina German
%A Christina Lissewski
%A Simona Coppola
%A Francesca Pantaleoni
%A Luisa Kocherscheid
%A Franziska Altmuller
%A Denny Schanze
%A Thushiha Logeswaran
%A Soheyla Chahrokh-Zadeh
%A Anna Munzig
%A Nakhaeirad, Saeideh
%A Helene Cave
%A Mohammad R. Ahmadian
%A Marco Tartaglia
%A Martin Zenker
%J Human Molecular Genetics
%@ 0964-6906
%D 2019

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