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
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
Changes of the switch region and remodeling of the active site of p.Gly23Val-MRAS after molecular dynamic simulations.
WT-MRAS (white) and p.Gly23Val-MRAS (red) variants are shown after 20-ns molecular dynamic simulations. Mutation-associated remodeling of the switch I and switch II regions as well as the nucleotide-binding site are noticeable by comparison. This missense mutation results in a marked attenuation of the distance between the T45 and G70 residues by 2.871A, resulting in these two residues being brought closer to the phosphate groups of the bound nucleotide and the magnesium ion.