Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy
Erin M. Higgins, … , Raul Urrutia, Michael J. Ackerman
Erin M. Higgins, … , Raul Urrutia, Michael J. Ackerman
Published March 9, 2017
Citation Information: JCI Insight. 2017;2(5):e91225. https://doi.org/10.1172/jci.insight.91225.
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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

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Figure 1

Whole exome sequencing and familial genomic triangulation for the elucidation of a genetic substrate for Noonan syndrome.

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Whole exome sequencing and familial genomic triangulation for the elucid...
(A) Noonan syndrome pedigree with presumed sporadic or autosomal recessive (compound heterozygous or homozygous) inheritance pattern showing the case-parent trio with the affected index case (black circle) and unaffected family members (white symbols). (B) Clinical appearance of the patient at 17 years old, showing facial characteristics of Noonan syndrome, such as long facies and low-set posteriorly rotated ears. Images were obtained and published with both patient’s and parents’ permission. (C) Parasternal long-axis view of the index case’s echocardiogram performed at age 8 (October 27, 2006) and age 17 (August 30, 2016). The echocardiogram shows left ventricular hypertrophy with maximal septal thickness of 18 and 17 mm for these 2 echocardiograms, respectively (Ao, aorta; LA, left atrium; LV, left ventricle). (D) A flow diagram of the variant filtering process following whole exome sequencing, and results for both a sporadic and autosomal recessive inheritance model.