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Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy.

  • Motta, Marialetizia1
  • Sagi-Dain, Lena2
  • Krumbach, Oliver H F3
  • Hahn, Andreas4
  • Peleg, Amir2
  • German, Alina5
  • Lissewski, Christina6
  • Coppola, Simona7
  • Pantaleoni, Francesca1
  • Kocherscheid, Luisa6
  • Altmüller, Franziska6
  • Schanze, Denny6
  • Logeswaran, Thushiha8
  • Chahrokh-Zadeh, Soheyla9
  • Munzig, Anna9
  • Nakhaei-Rad, Saeideh3
  • Cavé, Hélène10, 11
  • Ahmadian, Mohammad R3
  • Tartaglia, Marco1
  • Zenker, Martin6
  • 1 Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy. , (Italy)
  • 2 The Human Genetic institute, Carmel Medical Center, Ruth and Bruce Rappaport Faculty of Medicine, Israel Institute of Technology, Haifa, Israel. , (Israel)
  • 3 Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich Heine University, Düsseldorf, Germany. , (Germany)
  • 4 Department of Child Neurology, University Hospital, Gießen, Germany. , (Germany)
  • 5 Pediatric Department, Bnai-Zion Medical Center and Clalit Health Maintenance Organization, Haifa, Israel. , (Israel)
  • 6 Institute of Human Genetics, University Hospital, Magdeburg, Germany. , (Germany)
  • 7 National Centre for Rare Diseases, Istituto Superiore di Sanità, Rome, Italy. , (Italy)
  • 8 Pediatric Heart Center, University Hospital, Gießen, Germany. , (Germany)
  • 9 Center of Human Genetics and Laboratory Diagnostics, Martinsried, Germany. , (Germany)
  • 10 Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, 75019 Paris, France. , (France)
  • 11 INSERM UMR 1131, Institut de Recherche Saint-Louis, Université de Paris, 75010 Paris, France. , (France)
Published Article
Human Molecular Genetics
Oxford University Press
Publication Date
Jul 21, 2020
DOI: 10.1093/hmg/ddz108
PMID: 31108500


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. © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

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