RRC ID 56694
Author Takahara S, Inoue SI, Miyagawa-Tomita S, Matsuura K, Nakashima Y, Niihori T, Matsubara Y, Saiki Y, Aoki Y.
Title New Noonan syndrome model mice with RIT1 mutation exhibit cardiac hypertrophy and susceptibility to β-adrenergic stimulation-induced cardiac fibrosis.
Journal EBioMedicine
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 S100A4, 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 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.
Volume 42
Pages 43-53
Published 2019-4-1
DOI 10.1016/j.ebiom.2019.03.014
PII S2352-3964(19)30154-9
PMID 30898653
PMC PMC6491386
MeSH Abnormalities, Multiple / diagnosis Abnormalities, Multiple / genetics Adrenergic beta-Agonists Alleles Animals Cardiomegaly / diagnosis Cardiomegaly / etiology* Cardiomegaly / pathology* Disease Models, Animal Echocardiography Female Fibrosis Genetic Association Studies Genetic Loci Germ-Line Mutation Heart Function Tests Immunohistochemistry Kaplan-Meier Estimate Male Mice Mice, Transgenic Mutation* Noonan Syndrome / complications* Noonan Syndrome / diagnosis Noonan Syndrome / genetics* Noonan Syndrome / mortality Phenotype Proto-Oncogene Proteins c-akt / metabolism Signal Transduction ras Proteins / genetics*
IF 6.68
Times Cited 4
Mice RBRC01828