Two heterozygous mutations in NFATC1 in a patient with Tricuspid Atresia

Tricuspid Atresia (TA) is a rare form of congenital heart disease (CHD) with usually poor prognosis in humans. It presents as a complete absence of the right atrio-ventricular connection secured normally by the tricuspid valve. Defects in the tricuspid valve are so far not associated with any genetic locus, although mutations in numerous genes were linked to multiple forms of congenital heart disease. In the last decade, Knock-out mice have offered models for cardiologists and geneticists to study the causes of congenital disease. One such model was the Nfatc1(-/-) mice embryos which die at mid-gestation stage due to a complete absence of the valves. NFATC1 belongs to the Rel family of transcription factors members of which were shown to be implicated in gene activation, cell differentiation, and organogenesis. We have previously shown that a tandem repeat in the intronic region of NFATC1 is associated with ventricular septal defects. In this report, we unravel for the first time a potential link between a mutation in NFATC1 and TA. Two heterozygous missense mutations were found in the NFATC1 gene in one indexed-case out of 19 patients with TA. The two amino-acids changes were not found neither in other patients with CHDs, nor in the control healthy population. Moreover, we showed that these mutations alter dramatically the normal function of the protein at the cellular localization, DNA binding and transcriptional levels suggesting they are disease-causing.