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
Author Information
Marialetizia Motta: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Lena Sagi-Dain: The Human Genetic institute, Carmel Medical Center, Ruth and Bruce Rappaport Faculty of Medicine, Israel Institute of Technology, Haifa, Israel.
Oliver H F Krumbach: Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich Heine University, Düsseldorf, Germany.
Andreas Hahn: Department of Child Neurology, University Hospital, Gießen, Germany.
Amir Peleg: The Human Genetic institute, Carmel Medical Center, Ruth and Bruce Rappaport Faculty of Medicine, Israel Institute of Technology, Haifa, Israel.
Alina German: Pediatric Department, Bnai-Zion Medical Center and Clalit Health Maintenance Organization, Haifa, Israel.
Christina Lissewski: Institute of Human Genetics, University Hospital, Magdeburg, Germany.
Simona Coppola: National Centre for Rare Diseases, Istituto Superiore di Sanità, Rome, Italy.
Francesca Pantaleoni: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Luisa Kocherscheid: Institute of Human Genetics, University Hospital, Magdeburg, Germany.
Franziska Altmüller: Institute of Human Genetics, University Hospital, Magdeburg, Germany.
Denny Schanze: Institute of Human Genetics, University Hospital, Magdeburg, Germany.
Thushiha Logeswaran: Pediatric Heart Center, University Hospital, Gießen, Germany.
Soheyla Chahrokh-Zadeh: Center of Human Genetics and Laboratory Diagnostics, Martinsried, Germany.
Anna Munzig: Center of Human Genetics and Laboratory Diagnostics, Martinsried, Germany.
Saeideh Nakhaei-Rad: Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich Heine University, Düsseldorf, Germany.
Hélène Cavé: Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, 75019 Paris, France.
Mohammad R Ahmadian: Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich Heine University, Düsseldorf, Germany.
Marco Tartaglia: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Martin Zenker: Institute of Human Genetics, University Hospital, Magdeburg, Germany.
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.
