MRAS – Noonan syndrome

Noonan syndrome (Noonan syndrome) is an autosomal dominant developmental disorder characterized by short stature, facial dysmorphism and a high prevalence of hypertrophic cardiomyopathy (HCM). Germline gain-of-function mutations in RAS/MAPK pathway genes cause the RASopathies. The small GTPase gene MRAS has recently been implicated as a definitive Noonan syndrome-susceptibility gene with a distinctive HCM risk profile.

Initial trio whole-exome sequencing identified a de novo c.68G>T (p.Gly23Val) variant in a 15-year-old female and a second de novo c.203C>T (p.Thr68Ile) allele in one of 109 genotype-negative NS with HCM patients (2 probands) ([PMID:28289718]). Subsequent case reports described de novo c.212A>G (p.Gln71Arg) in a severe Noonan syndrome patient ([PMID:31173466]), de novo c.203C>T (p.Thr68Ile) in both a neonatal HCM case ([PMID:34080768]) and an adult subject with late-onset left ventricular hypertrophy and neuropsychiatric features ([PMID:36734411]), and de novo c.67G>C (p.Gly23Arg) in another infant ([PMID:31108500]), totaling 7 unrelated probands (PMID:28289718,31173466,31108500,34080768,36734411).

All reported MRAS variants arose de novo in heterozygous form, consistent with autosomal dominant inheritance, with no evidence of transmission in affected relatives (affected_relatives=0). No loss-of-function alleles have been observed; only recurrent missense substitutions cluster at codons Gly23, Thr68 and Gln71, with p.Thr68Ile observed in four independent individuals.

Functional studies demonstrate a clear gain-of-function mechanism. Molecular dynamics and in silico tools predicted disruption of GTPase effector interactions for p.Gly23Val, which exhibited a 40-fold increase in active GTP-bound MRAS and enhanced MAPK pathway signalling in ectopic expression assays ([PMID:28289718]). Human molecular genetics analyses of c.203C>T and c.67G>C mutants confirmed impaired GTPase activity, prolonged plasma membrane localization, and increased binding to PPP1CB and SHOC2 with downstream MAPK and PI3K-AKT hyperactivation ([PMID:31108500]). Patient-specific induced pluripotent stem cell-derived cardiomyocytes bearing p.Gly23Val showed marked hypertrophy, altered gene expression and abnormal calcium handling; CRISPR/Cas9 correction rescued these phenotypes and knock-in in control cells recapitulated them ([PMID:31638832]). Cryo-EM structure of the SHOC2-MRAS-PP1C holophosphatase complex elucidated how GTP-loaded MRAS engages SHOC2 and PP1C, rationalizing the effect of gain-of-function mutations ([PMID:35831509]).

No studies have disputed the MRAS–Noonan syndrome association. The concordance of de novo genetic findings with multiple orthogonal functional assays over >6 years supports a definitive clinical validity classification.

Clinically, MRAS should be included in diagnostic panels for Noonan syndrome and related RASopathies, especially in patients presenting with early-onset or severe HCM. Key take-home: MRAS gain-of-function missense variants cause a definitive autosomal dominant Noonan syndrome with high HCM risk, informing genetic diagnosis and potential MAPK-targeted therapies.

References

• JCI insight • 2017 • Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy. PMID:28289718
• American journal of medical genetics. Part A • 2019 • Severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant: a recurrent substitution in RAS homologs in various cancers. PMID:31173466
• American journal of medical genetics. Part A • 2021 • Atypical, severe hypertrophic cardiomyopathy in a newborn presenting Noonan syndrome harboring a recurrent heterozygous MRAS variant. PMID:34080768
• Human molecular genetics • 2020 • Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy. PMID:31108500
• Circulation. Genomic and precision medicine • 2019 • MRAS Variants Cause Cardiomyocyte Hypertrophy in Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Additional Evidence for MRAS as a Definitive Noonan Syndrome-Susceptibility Gene. PMID:31638832
• American journal of medical genetics. Part C, Seminars in medical genetics • 2023 • Natural history of MRAS-related Noonan syndrome: Evidence of mild adult-onset left ventricular hypertrophy and neuropsychiatric features. PMID:36734411
• Nature • 2022 • Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex. PMID:35831509

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