Elucidation of MRAS-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 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.

• Authors: Erin M Higgins, J Martijn Bos, Heather Mason-Suares, David J Tester, Jaeger P Ackerman, Calum A MacRae, Katia Sol-Church, Karen W Gripp, Raul Urrutia, Michael J Ackerman
• Journal: JCI insight (JCI Insight) Vol. 2 Issue 5 Pg. e91225 (03 09 2017) ISSN: 2379-3708 [Print] United States
• PMID: 28289718 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural)

Topics

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