title: Elucidation ofMRAS-mediated Noonan syndrome with cardiac hypertrophy.
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 inMRAS-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 ofMRASin 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, establishingMRASas the newest NS with cardiac hypertrophy-susceptibility gene.
authors.affiliation: Mayo Clinic Graduate School of Biomedical Sciences.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Higgins
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics and Windland Smith Rice Sudden Death Genomics Laboratory.|Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: J Martijn
authors.initials: JM
authors.lastname: Bos
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Mason-Suares
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics and Windland Smith Rice Sudden Death Genomics Laboratory.|Department of Cardiovascular Diseases/Division of Heart Rhythm Services, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics and Windland Smith Rice Sudden Death Genomics Laboratory.
authors.forename: Jaeger P
authors.initials: JP
authors.lastname: Ackerman
authors.affiliation: Divisions of Cardiovascular Medicine and Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Calum A
authors.initials: CA
authors.lastname: MacRae
authors.affiliation: Center for Applied Clinical Genomics and.
authors.forename: Katia
authors.initials: K
authors.lastname: Sol-Church
authors.affiliation: Center for Applied Clinical Genomics and.|Division of Medical Genetics, Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.
authors.forename: Karen W
authors.initials: KW
authors.lastname: Gripp
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.|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.
authors.forename: Raul
authors.initials: R
authors.lastname: Urrutia
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics and Windland Smith Rice Sudden Death Genomics Laboratory.|Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota, USA.|Department of Cardiovascular Diseases/Division of Heart Rhythm Services, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D006332:Cardiomegaly / Q000150:complications / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D011905:Genes, ras; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D056004:Molecular Dynamics Simulation; D009634:Noonan Syndrome / Q000150:complications / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D000073359:Exome Sequencing; D055815:Young Adult