Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect

Human Mutation
Rosangela FereseA De Luca

Abstract

Atrioventricular septal defect (AVSD) may occur as part of a complex disorder (e.g., Down syndrome, heterotaxy), or as isolate cardiac defect. Multiple lines of evidence support a role of calcineurin/NFAT signaling in AVSD, and mutations in CRELD1, a protein functioning as a regulator of calcineurin/NFAT signaling have been reported in a small fraction of affected subjects. In this study, 22 patients with isolated AVSD and 38 with AVSD and heterotaxy were screened for NFATC1 gene mutations. Sequence analysis identified three missense variants in three individuals, including a subject with isolated AVSD [p.(Ala367Val)], an individual with AVSD and heterotaxy [p.(Val210Met)], and a subject with AVSD, heterotaxy, and oculo-auriculo-vertebral spectrum (OAVS) [p.(Ala696Thr)], respectively. The latter was also heterozygous for a missense change in TBX1 [p.(Pro86Leu)]. Targeted resequencing of genes associated with AVSD, heterotaxy, or OAVS excluded additional hits in the three mutation-positive subjects. Functional characterization of NFATC1 mutants documented defective nuclear translocation and decreased transcriptional transactivation activity. When expressed in zebrafish, the three NFATC1 mutants caused cardiac looping defects and...Continue Reading

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Citations

Mar 3, 2019·Biomedicines·Panagiota Giardoglou, Dimitris Beis
Feb 20, 2020·Circulation Research·Felix GunawanAnabela Bensimon-Brito
May 15, 2020·Italian Journal of Pediatrics·Flaminia PugnaloniPaolo Versacci
Apr 10, 2021·ESC Heart Failure·Andrea FrustaciMatteo Antonio Russo

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