{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T11:45:16Z","timestamp":1774266316640,"version":"3.50.1"},"reference-count":67,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2019,5,21]],"date-time":"2019-05-21T00:00:00Z","timestamp":1558396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"German Federal Ministry of Education and Research","award":["01GM1519D"],"award-info":[{"award-number":["01GM1519D"]}]},{"name":"German Federal Ministry of Education and Research","award":["01GM1902C"],"award-info":[{"award-number":["01GM1902C"]}]},{"name":"German Federal Ministry of Education and Research","award":["01GM1519A"],"award-info":[{"award-number":["01GM1519A"]}]},{"name":"NSEuroNet","award":["01GM1602B"],"award-info":[{"award-number":["01GM1602B"]}]},{"name":"NSEuroNet","award":["01GM1602A"],"award-info":[{"award-number":["01GM1602A"]}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["ZE 524\/10-1"],"award-info":[{"award-number":["ZE 524\/10-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005010","name":"AIRC","doi-asserted-by":"publisher","award":["IG 21614"],"award-info":[{"award-number":["IG 21614"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Italian Ministry of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u2009&amp;gt;\u2009T (p.Thr68Ile) and c.67G\u2009&amp;gt;\u2009C (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.<\/jats:p>","DOI":"10.1093\/hmg\/ddz108","type":"journal-article","created":{"date-parts":[[2019,5,15]],"date-time":"2019-05-15T19:15:27Z","timestamp":1557947727000},"page":"1772-1783","source":"Crossref","is-referenced-by-count":44,"title":["Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy"],"prefix":"10.1093","volume":"29","author":[{"given":"Marialetizia","family":"Motta","sequence":"first","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lena","family":"Sagi-Dain","sequence":"additional","affiliation":[{"name":"The Human Genetic institute, Carmel Medical Center, Ruth and Bruce Rappaport Faculty of Medicine, Israel Institute of Technology, Haifa, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver H F","family":"Krumbach","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich Heine University, D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Hahn","sequence":"additional","affiliation":[{"name":"Department of Child Neurology, University Hospital, Gie\u00dfen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amir","family":"Peleg","sequence":"additional","affiliation":[{"name":"The Human Genetic institute, Carmel Medical Center, Ruth and Bruce Rappaport Faculty of Medicine, Israel Institute of Technology, Haifa, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alina","family":"German","sequence":"additional","affiliation":[{"name":"Pediatric Department, Bnai-Zion Medical Center and Clalit Health Maintenance Organization, Haifa, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Lissewski","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital, Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"Coppola","sequence":"additional","affiliation":[{"name":"National Centre for Rare Diseases, Istituto Superiore di Sanit\u00e0, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Pantaleoni","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luisa","family":"Kocherscheid","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital, Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franziska","family":"Altm\u00fcller","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital, Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denny","family":"Schanze","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital, Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thushiha","family":"Logeswaran","sequence":"additional","affiliation":[{"name":"Pediatric Heart Center, University Hospital, Gie\u00dfen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soheyla","family":"Chahrokh-Zadeh","sequence":"additional","affiliation":[{"name":"Center of Human Genetics and Laboratory Diagnostics, Martinsried, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Munzig","sequence":"additional","affiliation":[{"name":"Center of Human Genetics and Laboratory Diagnostics, Martinsried, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saeideh","family":"Nakhaei-Rad","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich Heine University, D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H\u00e9l\u00e8ne","family":"Cav\u00e9","sequence":"additional","affiliation":[{"name":"Assistance Publique des H\u00f4pitaux de Paris (AP-HP), H\u00f4pital Robert Debr\u00e9, D\u00e9partement de G\u00e9n\u00e9tique, 75019 Paris, France"},{"name":"INSERM UMR 1131, Institut de Recherche Saint-Louis, Universit\u00e9 de Paris, 75010 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad R","family":"Ahmadian","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich Heine University, D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Zenker","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital, Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,5,21]]},"reference":[{"key":"2020072105163776400_ref1","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/j.1749-6632.2010.05790.x","article-title":"Disorders of dysregulated signal traffic through the RAS-MAPK pathway: 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