Maria I. Kontaridis, PhD

Developmental Effects of PTPN11 Mutations on Pediatric Hypertrophic Cardiomyopathy
Beth Israel Deaconess Medical Center, Boston, MA
Maria I. Kontaridis, PhD – $50,000

Mutations in PTPN11, a gene encoding an enzyme protein called SHP2, are directly responsible for hypertrophic cardiomyopathy (HCM). Mutations in SHP2 have been linked to nearly all cases of a disorder called LEOPARD Syndrome (LS), which involves HCM in more than 90% of cases. Under normal conditions, SHP2 serves as a regulatory enzyme that controls important cellular signaling events that determine whether cells continue to grow or to die. Because SHP2 plays such an important role in normal cell regulatory processes, mutations in SHP2 (such as those that cause LS) likely evoke abnormal signaling events during cardiac development that lead to the development of HCM in children. This study will determine how PTPN11 mutations disrupt heart function and cause HCM. Specifically, the study will 1) determine the effects of LS expression in important cell types present in the heart during development to assess which of these cell types contribute the most to the development of HCM in children; 2) analyze the formation of the heart structures and determine heart function in each of the LS cell types; and 3) determine the functional mechanisms of the cause of HCM in LS by assessing whether the LS mutation causes abnormal signaling events during heart development. Findings will both provide novel insights into the function of SHP2 and its mutations in the development of HCM in children and serve as a stepping stone to identifying potential therapies not only for patients with LS-associated HCM, but also for pediatric patients with other types of HCM as well.