Background: Hypertrophic cardiomyopathy (HCM) is the frequent cardiac phenotype in Noonan syndrome (NS) and LEOPARD syndrome (LS). We have recently demonstrated a possible correlation between phenotype of cardiac hypertrophy and phosphatase activities of SHP2, a product of the PTPN11 gene in NS and LS. The aim of the current study is to investigate whether SHP2 mutants could induce different types of cardiac myocyte hypertrophy in vitro.
Methods: Patients (n=8) with HCM in NS or LS were screened for mutations in the PTPN11 gene. The six mutations were isolated and cloned into a pAd DEST/V5 vector. Neonatal rat cardiomyocyte were isolated and infected. We performed the quantitative morphometry (surface area) in each cardiomyocyte and investigate the signal transduction pathways responsible for the cardiac hypertrophy.
Results: WT(wild type)-SHP2 expressed cardiomyocyte showed significant increase in length and surface area compared to control (LacZ-expressed, p<0.01). LS mutant (Y279C, Q510E) caused more remarkable increase in surface area of cardiomyocyte than WT (p<0.01). Among several signaling, only pStat3 after LIF stimulation could be activated in Y279C and Q510E, whereas significantly not activated in WT and D61N.
Summary: All SHP2 mutants induced hypertrophic changes in cardiomyocyte in vitro. LS mutants with severe HOCM induced more significant changes in surface area of cardiomyocyte. Low phosphatase activity of SHP2 in cardiomyocyte may affect the severity of cell hypertrophy via unknown pathway other than LIF-Stat pathway. We need further study to elucidate a key role of SHP2 in cardiomyocytes.