A novel role for NFATC1 gene in patients with both congenital heart diseases and eye defects -

Abstract

Valvulogenesis and eye development are among the most intriguing events during development. Complex signaling hierarchies of transcription and growth factors orchestrate such developmental processes. Among these modulators, NFATC1 (Nuclear Factor of Activated T-cells), VEGF (Vascular Endothelial Growth Factor), TBX5 (T- box transcription factor), and calcineurin are known to be key players implicated in development. Investigating the role of NFATC1 and unveiling its downstream targets and co-operators, are crucial in order to understand the pathological context of valvuloseptal and congenital eye defects. We have recently shown two novel missense (P66L, I701L) mutations in the NFATC1 gene in one patient with tricuspid atresia. Functional analyses did show a defect in its cellular localization, transcriptional activities and DNA binding activity of the protein. Moreover, previous data form our lab have correlated a defective valvular and septal phenotype of aortic stenosis and atrial septal defect to a heterozygous mutation in the TBX5 gene. Our preliminary data suggests also that the interaction between NFATC1-TBX5 and TBX5-calcineurin boosts the transcriptional activity of VEGF promoter. We screened for mutations in the coding region of NFATC1 in a family with septal and valve defects in addition to severe eye defects and found a previously documented polymorphism (rs62096875) leading to a missense mutation (V210M). Our results unravel a novel pathway implicating an interaction with Tbx5, probably responsible for the underlying phenotype. We can confidently suggest that NFATC1 plays a major role in congenital valvular diseases and eye defects. We hypothesize according to our result that the vascular endothelial growth factor (VEGF) is a downstream target for both NFATC1 and Tbx5 and is implicated both in heart and eye development.