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Dysregulation of the RAS\/mitogen\u2010activated protein kinase (MAPK) pathway is a common molecular mechanism underlying the pathogenesis of these disorders. Germline mutations in\n                      <jats:italic>RIT1<\/jats:italic>\n                      have also been identified in patients with Noonan syndrome. Patients with\n                      <jats:italic>RIT1<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated the cardiovascular and lymphatic phenotypes of\n                      <jats:italic>Rit1<\/jats:italic>\n                      <jats:sup>A57G\/+<\/jats:sup>\n                      embryos. To elucidate that the activation of MEK\/ERK is the involvement of cardiac abnormalities in\n                      <jats:italic>Rit1<\/jats:italic>\n                      <jats:sup>A57G\/+<\/jats:sup>\n                      embryos, we administered a MEK1\/2 inhibitor to\n                      <jats:italic>Rit1<\/jats:italic>\n                      <jats:sup>A57G\/+<\/jats:sup>\n                      embryos and investigated the cardiovascular phenotypes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      At E16.5,\n                      <jats:italic>Rit1<\/jats:italic>\n                      <jats:sup>A57G\/+<\/jats:sup>\n                      embryos exhibited cardiac hypertrophy without cardiomyocyte hypertrophy and demonstrated progressive cell proliferation. Furthermore,\n                      <jats:italic>Rit1<\/jats:italic>\n                      <jats:sup>A57G\/+<\/jats:sup>\n                      embryos exhibited pulmonary valve stenosis and lymphatic vessel expansion. Maternal intraperitoneal injection of PD0325901, a MEK1\/2 inhibitor, prevented cardiac hypertrophy in\n                      <jats:italic>Rit1<\/jats:italic>\n                      <jats:sup>A57G\/+<\/jats:sup>\n                      embryos.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Rit1<\/jats:italic>\n                      mutation causes cardiovascular and lymphatic abnormalities in the fetal period, and that the activation of MEK\/ERK is the potential pathogenesis of cardiac hypertrophy.\n                    <\/jats:p>\n                  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