Phenotypic Analysis of Embryos in a Noonan Syndrome Model Mouse With the Rit1 A57G Mutation

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ABSTRACT Background Noonan syndrome is a congenital genetic disorder characterized by distinctive craniofacial features, short stature, and congenital heart disease. Dysregulation of the RAS/mitogen‐activated protein kinase (MAPK) pathway is a common molecular mechanism underlying the pathogenesis of these disorders. Germline mutations in RIT1 have also been identified in patients with Noonan syndrome. Patients with RIT1 mutations frequently exhibit cardiovascular abnormalities such as hypertrophic cardiomyopathy and lymphatic disorders. However, it remains unclear when cardiovascular abnormalities and lymphatic disorders develop and whether these disorders influence prognosis during the fetal period. Methods We investigated the cardiovascular and lymphatic phenotypes of Rit1 A57G/+ embryos. To elucidate that the activation of MEK/ERK is the involvement of cardiac abnormalities in Rit1 A57G/+ embryos, we administered a MEK1/2 inhibitor to Rit1 A57G/+ embryos and investigated the cardiovascular phenotypes. Results At E16.5, Rit1 A57G/+ embryos exhibited cardiac hypertrophy without cardiomyocyte hypertrophy and demonstrated progressive cell proliferation. Furthermore, Rit1 A57G/+ embryos exhibited pulmonary valve stenosis and lymphatic vessel expansion. Maternal intraperitoneal injection of PD0325901, a MEK1/2 inhibitor, prevented cardiac hypertrophy in Rit1 A57G/+ embryos. Conclusions Rit1 mutation causes cardiovascular and lymphatic abnormalities in the fetal period, and that the activation of MEK/ERK is the potential pathogenesis of cardiac hypertrophy.

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