Abstract 181: Rescue of the Cardiac Phenotype of Noonan Syndrome In Vivo by Ablation of Cardiac ERK1/2 Signaling
Mutations within SHP2, a protein tyrosine phosphatase, cause a large proportion of Noonan syndrome (NS) cases. Cardiac heart disease presents in approximately 80–90% of these patients. A spectrum of morphological and functional cardiac deficits, with the most common being dysplastic pulmonary valve, AV septal defects or hypertrophic cardiomyopathy, presents in 80 –90% of these patients. One of the many mutations found in SHP2, Q79R, results in a gain of function. To elucidate the pathogenic role of Q79R on the embryonic and postnatal heart, we performed in vivo analyses using cardiomyocyte-specific transgenic expression before or after birth. We expressed the wild type (WT) or mutant (Q79R) mouse SHP2 cDNAs using either the beta-or alpha- myosin heavy chain (MHC) promoters (embryonic and fetal ventricular cardiomyocytes, post-birth heart, respectively). Late embryonic (E16.5) hearts with Q79R SHP2 expression showed ventricular noncompaction and ventricular septal defects (VSDs). Ventricular noncompaction persisted in the adults with 26% of the mice dying of congestive heart failure by 7 months. In contrast, neither the alpha-MHC Q79R nor beta-MHC WT SHP2 embryonic or adult hearts showed any abnormalities. Echocardiography of beta-MHC Q79R SHP2 mice at 3 months demonstrated ventricular dilatation, wall thinning and decreased contractility, whereas cardiac function in the alpha-MHC Q79R and beta-MHC WT SHP2 mice was normal. To explore the mechanism of the resulting embryonic pathology, we searched for activation/deactivation of canonical signaling pathways. ERK1/2 hyperphosphorylation in the beta-MHC Q79R SHP2 heart occurred transiently in the embryonic stage resulting in enhanced cardiomyocyte proliferation. Crossing the beta-MHC Q79R SHP2 mice into ERK1 and ERK2 knockout mice ameliorated ventricular noncompaction, VSD and restored normal cardiac function. Cardiomyocyte hyperproliferation also returned to normal. Our data confirm the developmental-specific effects of Q79R and suggest that ERK1/2 signaling causes enhanced cardiomyocyte proliferation, resulting in cardiac malformations.