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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 2018

See all articles by Shingo Takahara

Shingo Takahara

Tohoku University - Graduate School of Medicine

Shin-ichi Inoue

Tohoku University - Department of Medical Genetics

Sachiko Miyagawa-Tomita

Tokyo Womens Medical University

Katsuhisa Matsuura

Tokyo Womens Medical University

Yasumi Nakashima

Seirei Hamamatsu General Hospital

Tetsuya Niihori

Tohoku University - Graduate School of Medicine

Yoichi Matsubara

Tohoku University - Graduate School of Medicine

Yoshikatsu Saiki

Tohoku University

Yoko Aoki

Tohoku University - Department of Medical Genetics

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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 (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

Suggested Citation

Takahara, Shingo and Inoue, Shin-ichi and Miyagawa-Tomita, Sachiko and Matsuura, Katsuhisa and Nakashima, Yasumi and Niihori, Tetsuya and Matsubara, Yoichi and Saiki, Yoshikatsu and Aoki, Yoko, New Noonan Syndrome Model Mice with RIT1 Mutation Exhibit Cardiac Hypertrophy and Susceptibility to β-adrenergic Stimulation-Induced Cardiac Fibrosis (October 12, 2018). EBioMedicine, Volume 42, April 2019, Pages 43-53, https://doi.org/10.1016/j.ebiom.2019.03.014, Available at SSRN: https://ssrn.com/abstract=3299117 or http://dx.doi.org/10.2139/ssrn.3299117

Shingo Takahara

Tohoku University - Graduate School of Medicine

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Shin-ichi Inoue (Contact Author)

Tohoku University - Department of Medical Genetics ( email )

Sendai, 980-8574
Japan

Sachiko Miyagawa-Tomita

Tokyo Womens Medical University

8-1 Kawadacho
Shinjuku
Tokyo, 162-8666
Japan

Katsuhisa Matsuura

Tokyo Womens Medical University

8-1 Kawadacho
Shinjuku
Tokyo, 162-8666
Japan

Yasumi Nakashima

Seirei Hamamatsu General Hospital

Hamamatsu
Japan

Tetsuya Niihori

Tohoku University - Graduate School of Medicine

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Yoichi Matsubara

Tohoku University - Graduate School of Medicine

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Yoshikatsu Saiki

Tohoku University

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Yoko Aoki

Tohoku University - Department of Medical Genetics ( email )

Sendai, 980-8574
Japan

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