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Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy. JCI Insight 2017 Mar 09;2(5):e91225

Date

03/16/2017

Pubmed ID

28289718

Pubmed Central ID

PMC5333962

DOI

10.1172/jci.insight.91225

Scopus ID

2-s2.0-85063284454 (requires institutional sign-in at Scopus site)   62 Citations

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.

Author List

Higgins EM, Bos JM, Mason-Suares H, Tester DJ, Ackerman JP, MacRae CA, Sol-Church K, Gripp KW, Urrutia R, Ackerman MJ

Author

Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Amino Acid Sequence
Cardiomegaly
Child
Child, Preschool
Female
Genes, ras
HEK293 Cells
Humans
Infant
Infant, Newborn
Male
Middle Aged
Molecular Dynamics Simulation
Noonan Syndrome
Sequence Homology, Amino Acid
Young Adult