NFATC1 and PAX pathway in cardiac and ocular diseases -

Abstract

The cardiac valvular and septal malformations account for the majority of the congenital heart defects (CHD). Processes that govern the heart development have been studied thoroughly through the last decade, however little is known about specific interactions that lead to the normal heart formation. Nuclear factor of activated T cells (NFAT) signaling and Vascular Endothelial Growth Factor (VEGF) have been shown to be main players in valve formation. NFATC1 knockout mice did not develop aortic and pulmonary valves and died of congestive heart failure. These studies revealed a pivotal role of NFATC1 in heart valve formation.Our hypothesis is that novel mutation within the NFATC1 gene lead to defects that affect the protein at different levels so we aim to functionally characterization this novel point mutation (P68L) of NFATC1 at three different levels: - Translocation of NFATC1 to nucleus. - Transcriptional Regulation - Interaction with calcineurin. We hypothesize that this novel P68L mutation in the NFATC1 gene is disease causing and CHD contributing. We suggest that the mutation will distort the expression of VEGF and disrupt the physical interaction of NFATC1 protein with calcineurin. Our second hypothesis is related to a previous study have been done in our lab revealed a potential role for NFATC1 gene in the context of valve and eye development. To understand how this previously documented V210M NFATC1 mutant affects the heart and the ocular development process. We hypothesize a physical interaction between NFATC1 and transcription factor PAX6 that has been considered as a master gene in eye development. The newly identified NFATC1 mutation P68L in patient with an atrial septal defect resulted in different biophysical properties than that of the wild type NFATC1 and the P68T mutant that has been found in normal population. P68L and P68T affect the subcellular localization of the NFATC1 protein induced by calcineurin, as well as decreased interactions with calcineurin compared to the wild type NFATC1.