New Noonan syndrome model mice with RIT1 mutation exhibit cardiac hypertrophy and susceptibility to β-adrenergic stimulation-induced cardiac fibrosis

Shingo Takahara, Shin ichi Inoue, Sachiko Miyagawa-Tomita, Katsuhisa Matsuura, Yasumi Nakashima, Tetsuya Niihori, Yoichi Matsubara, Yoshikatsu Saiki, Yoko Aoki

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)43-53
Number of pages11
JournalEBioMedicine
Volume42
DOIs
Publication statusPublished - 2019 Apr

Keywords

  • AKT
  • Cardiac fibrosis
  • Cardiac hypertrophy
  • Noonan syndrome
  • RIT1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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