2. Academic Validation
  3. Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy

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

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.
PMID: 28289718 DOI: 10.1172/jci.insight.91225
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.

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