{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T15:06:25Z","timestamp":1790003185584,"version":"4.0.1"},"reference-count":68,"publisher":"American Society for Clinical Investigation","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,3,9]]},"abstract":"<jats:p>\n                    Noonan syndrome (NS; MIM 163950) is an autosomal dominant disorder and a member of a family of developmental disorders termed \u201cRASopathies,\u201d which are caused mainly by gain-of-function mutations in genes encoding RAS\/MAPK signaling pathway proteins. Whole exome sequencing (WES) and trio-based genomic triangulation of a 15-year-old female with a clinical diagnosis of NS and concomitant cardiac hypertrophy and her unaffected parents identified a de novo variant in\n                    <jats:italic>MRAS<\/jats:italic>\n                    -encoded RAS-related protein 3 as the cause of her disease. Mutation analysis using in silico mutation prediction tools and molecular dynamics simulations predicted the identified variant, p.Gly23Val-MRAS, to be damaging to normal protein function and adversely affect effector interaction regions and the GTP-binding site. Subsequent ectopic expression experiments revealed a 40-fold increase in MRAS activation for p.Gly23Val-MRAS compared with WT-MRAS. Additional biochemical assays demonstrated enhanced activation of both RAS\/MAPK pathway signaling and downstream gene expression in cells expressing p.Gly23Val-MRAS. Mutational analysis of\n                    <jats:italic>MRAS<\/jats:italic>\n                    in a cohort of 109 unrelated patients with phenotype-positive\/genotype-negative NS and cardiac hypertrophy yielded another patient with a sporadic de novo MRAS variant (p.Thr68Ile, c.203C&gt;T). Herein, we describe the discovery of mutations in MRAS in patients with NS and cardiac hypertrophy, establishing\n                    <jats:italic>MRAS<\/jats:italic>\n                    as the newest NS with cardiac hypertrophy-susceptibility gene.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.91225","type":"journal-article","created":{"date-parts":[[2017,3,8]],"date-time":"2017-03-08T11:01:03Z","timestamp":1488970863000},"source":"Crossref","is-referenced-by-count":83,"title":["Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy"],"prefix":"10.1172","volume":"2","author":[{"given":"Erin M.","family":"Higgins","sequence":"first","affiliation":[{"name":"Mayo Clinic Graduate School of Biomedical Sciences,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Martijn","family":"Bos","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics and Windland Smith Rice Sudden Death Genomics Laboratory,"},{"name":"Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0146-4881","authenticated-orcid":true,"given":"Heather","family":"Mason-Suares","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts, USA."},{"name":"Department of Pathology, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Tester","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics and Windland Smith Rice Sudden Death Genomics Laboratory,"},{"name":"Department of Cardiovascular Diseases\/Division of Heart Rhythm Services, Mayo Clinic, Rochester, Minnesota, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaeger P.","family":"Ackerman","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics and Windland Smith Rice Sudden Death Genomics Laboratory,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5181-2664","authenticated-orcid":true,"given":"Calum A.","family":"MacRae","sequence":"additional","affiliation":[{"name":"Divisions of Cardiovascular Medicine and Network Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA."},{"name":"Harvard Stem Cell Institute, Cambridge, Massachusetts, USA."},{"name":"Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Broad Institute of MIT and Harvard, 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