New Noonan Syndrome Model Mice with RIT1 Mutation Exhibit Cardiac Hypertrophy and Susceptibility to β-adrenergic Stimulation-Induced Cardiac Fibrosis
52 Pages Posted: 13 Dec 2018More...
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 (Rit1A57G/＋). We investigated the phenotypes of Rit1A57G/＋ mice in fetal and adult stages as well as the effects of isoproterenol on cardiac function in Rit1A57G/＋ mice.
Findings: Rit1A57G/＋ embryos exhibited decreased viability, edema, subcutaneous hemorrhage and AKT activation. Surviving Rit1A57G/＋ mice had a short stature, craniofacial abnormalities and splenomegaly. Cardiac hypertrophy and cardiac fibrosis with increased expression of vimentin and periostin were observed in Rit1A57G/＋ mice compared to Rit1＋/＋ mice. Upon isoproterenol stimulation, cardiac fibrosis was drastically increased in Rit1A57G/＋ mice. Phosphorylated (at Thr308) AKT levels were also elevated in isoproterenol-treated Rit1A57G/＋ hearts.
Interpretation: The A57G mutation in Rit1 causes cardiac hypertrophy, fibrosis and other NS19 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.
Funding Statement: 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.
Declaration of Interests: The authors have declared that no conflict of interest exists.
Ethics Approval Statement: All animal experiments were approved by the Animal Care and Use Committee of Tohoku University (2018MdA-090, 2018MdA-022), which conforms NIH guidelines (Guide for the Care and Use of Laboratory Animals, Eighth Edition).
Keywords: Noonan syndrome, RIT1, cardiac hypertrophy, cardiac fibrosis, AKT
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