@article{10.1172/jci.insight.91225, author = {Erin M. Higgins AND J. Martijn Bos AND Heather Mason-Suares AND David J. Tester AND Jaeger P. Ackerman AND Calum A. MacRae AND Katia Sol-Church AND Karen W. Gripp AND Raul Urrutia AND Michael J. Ackerman}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy}, year = {2017}, month = {3}, volume = {2}, url = {https://insight.jci.org/articles/view/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.}, number = {5}, doi = {10.1172/jci.insight.91225}, url = {https://doi.org/10.1172/jci.insight.91225}, }