Background: Noonan syndrome (NS)is a genetic disorder characterized by short stature, a distinctive facial appearance, and heart defects. We recently discovered a novel NS gene, RIT1, which is a member of the RAS subfamily of small GTPases. NS patients with RIT1 mutations have a high incidence of hypertrophic cardiomyopathy and edematous phenotype, but the specific role of RIT1 remains unclear. Methods: To investigate how germline RIT1 mutations cause NS, we generated knock-in mice that carried a NS-associated Rit1 A57G mutation (Rit1 A57G/+ ). We investigated the phenotypes of Rit1 A57G/+ mice in fetal and adult stages as well as the effects of isoproterenol on cardiac function in Rit1 A57G/+ mice. Findings: Rit1 A57G/+ embryos exhibited decreased viability, edema, subcutaneous hemorrhage and AKT activation. Surviving Rit1 A57G/+ mice had a short stature, craniofacial abnormalities and splenomegaly. Cardiac hypertrophy and cardiac fibrosis with increased expression of S100A4, vimentin and periostin were observed in Rit1 A57G/+ mice compared to Rit1 +/+ mice. Upon isoproterenol stimulation, cardiac fibrosis was drastically increased in Rit1 A57G/+ mice. Phosphorylated (at Thr308)AKT levels were also elevated in isoproterenol-treated Rit1 A57G/+ hearts. Interpretation: The A57G mutation in Rit1 causes cardiac hypertrophy, fibrosis and other NS-associated features. Biochemical analysis indicates that the AKT signaling pathway might be related to downstream signaling in the RIT1 A57G mutant at a developmental stage and under β-adrenergic stimulation in the heart. Fund: The Grants-in-Aid were provided by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development, the Japan Society for the Promotion of Science KAKENHI Grant.
- Cardiac fibrosis
- Cardiac hypertrophy
- Noonan syndrome
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)