Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy PMID: 28289718

ADC Targets in Oncology

2026-04-10

Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy

JCI Insight. 2017 Mar 9;2(5):e91225. doi: 10.1172/jci.insight.91225.

Erin M Higgins ¹ , J Martijn Bos ² ³ , Heather Mason-Suares ⁴ ⁵ , David J Tester ² ⁶ , Jaeger P Ackerman ² , Calum A MacRae ⁷ ⁸ ⁹ ¹⁰ , Katia Sol-Church ¹¹ , Karen W Gripp ¹¹ ¹² , Raul Urrutia ¹³ ¹⁴ , Michael J Ackerman ² ³ ⁶

Affiliations

1. Mayo Clinic Graduate School of Biomedical Sciences.
2. Department of Molecular Pharmacology and Experimental Therapeutics and Windland Smith Rice Sudden Death Genomics Laboratory.
3. Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota, USA.
4. Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts, USA.
5. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
6. Department of Cardiovascular Diseases/Division of Heart Rhythm Services, Mayo Clinic, Rochester, Minnesota, USA.
7. Divisions of Cardiovascular Medicine and Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
8. Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
9. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
10. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
11. Center for Applied Clinical Genomics and.
12. Division of Medical Genetics, Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.
13. Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.
14. Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine, Laboratory of Epigenetics and Chromatin Dynamics, Epigenomics Translational Program, Gastroenterology Research Unit, Mayo Clinic, Rochester, Minnesota, USA.

Abstract

Noonan syndrome (NS; MIM 163950) is an autosomal dominant disorder and a member of a family of developmental disorders termed "RASopathies," 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 MRAS-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 MRAS 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>T). Herein, we describe the discovery of mutations in MRAS in patients with NS and cardiac hypertrophy, establishing MRAS as the newest NS with cardiac hypertrophy-susceptibility gene.