| First Author | Takahara S | Year | 2019 |
| Journal | EBioMedicine | Volume | 42 |
| Pages | 43-53 | PubMed ID | 30898653 |
| Mgi Jnum | J:277548 | Mgi Id | MGI:6330987 |
| Doi | 10.1016/j.ebiom.2019.03.014 | Citation | Takahara S, et al. (2019) New Noonan syndrome model mice with RIT1 mutation exhibit cardiac hypertrophy and susceptibility to beta-adrenergic stimulation-induced cardiac fibrosis. EBioMedicine 42:43-53 |
| abstractText | 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 beta-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. |
