Two Heterozygous Mutations in NFATC1 in a Patient with Tricuspid Atresia

Abstract

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.

Heterozygous missense mutations inNFATC1are associated with atrioventricular septal defect

“…The identified missense changes result in a variably defective NFATC1 nuclear import and transcriptional function in vitro, and dramatically impact cardiac development in vivo, supporting their functional and clinical relevance. These results are in agreement with previous studies reporting the identification of NFATC1 variants and CNVs encompassing the gene in patients with various congenital heart defects, including ventricular septal defects and tricuspid atresia (Abdul‐Sater et al., ; Feng et al., ; Gu et al., ; Han et al., ; Khalil et al., ; Li et al., ; Shen et al., ; Wang et al., ; Yehya, Souki, Bitar, & Nemer, ; Zhao et al., ). These results are also in agreement with previous identification of AVSD‐related variants in CRELD1 , a gene acting as a regulator of calcineurin/NFATC1 signaling by promoting NFATC1 dephosphorylation and translocation to the nucleus.…”

Nfatc1 directs the endocardial progenitor cells to make heart valve primordium

“…Genomic alterations in the NFATc1 locus have been identified in patients with CHD (Yehya et al, 2006) and recently, heterozygous mutations in NFATc1 have been identified in a patient with tricuspid atresia (Abdul-Sater et al, 2012). Further research is necessary to determine whether additional point mutations in NFATC1 and its regulatory genes in the NFATC1 signaling pathway (Crabtree and Olson, 2002; Rao, 2009) are associated with congenital heart valve malformations.…”

A Nonsense GATA6 Mutation Explains History of Congenital Heart Defects and 10 Years of Poorly-Controlled Diabetes Lacking DKA in a Non-Obese 30 Year-Old Incidentally Found to Have Pancreatic Hypoplasia

“…The pathogenesis of TA remains unknown, though an underlying genetic cause is suspected in at least some cases, supported by evidence from mice studies (14-16) as well as familial cases (17). A recent clinical genetic study of a patient with tricuspid atresia revealed two heterozygous mutations in NFATC1 (12), a gene previously discovered to be essential in valvular formation in mice (15)(16). Exocrine function was thought to be maintained in our patient as she had no history of weight loss or steatorrhea.…”

“…Tricuspid atresia (TA) is a rare cardiac malformation, representing only 1% of all congenital heart disease (12)(13). TA is a cyanotic malformation that presents as an absence of the tricuspid valve, effectively removing the direct conduit between the right atrium and ventricle (12). The pathogenesis of TA remains unknown, though an underlying genetic cause is suspected in at least some cases, supported by evidence from mice studies (14-16) as well as familial cases (17).…”