Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy

JCI Insight. 2017 Mar 9;2(5):e91225. 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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Cardiomegaly / complications
  • Cardiomegaly / genetics*
  • Child
  • Child, Preschool
  • Exome Sequencing
  • Female
  • Genes, ras*
  • HEK293 Cells
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Middle Aged
  • Molecular Dynamics Simulation
  • Noonan Syndrome / complications
  • Noonan Syndrome / genetics*
  • Sequence Homology, Amino Acid
  • Young Adult