Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy.
Authors | |
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. |
Year of Publication | 2017
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Journal | JCI Insight
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Volume | 2
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Issue | 5
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Pages | e91225
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Date Published | 2017 Mar 09
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ISSN | 2379-3708
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DOI | 10.1172/jci.insight.91225
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PubMed ID | 28289718
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PubMed Central ID | PMC5333962
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Links | |
Grant list | R01 DK052913 / DK / NIDDK NIH HHS / United States
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