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Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect.

Hum. Mutat.2018 Oct;39(10):1428-1441. doi:10.1002/humu.23593. Epub 2018 Jul 30
Rosangela Ferese 1 , Monica Bonetti 2 , Federica Consoli 3 , Valentina Guida 3 , Anna Sarkozy 3 , Francesca Romana Lepri 4 , Paolo Versacci 5 , Stefano Gambardella 1 , Giulio Calcagni 4 , Katia Margiotti 3 , Francesca Piceci Sparascio 3 , Hossein Hozhabri 6 , Tommaso Mazza 7 , Maria Cristina Digilio 4 , Bruno Dallapiccola 4 , Marco Tartaglia 4 , Bruno Marino 5 , Jeroen den Hertog 8 , Alessandro De Luca 3
Rosangela Ferese 1 , Monica Bonetti 2 , Federica Consoli 3 , Valentina Guida 3 , Anna Sarkozy 3 , Francesca Romana Lepri 4 , Paolo Versacci 5 , Stefano Gambardella 1 , Giulio Calcagni 4 , Katia Margiotti 3 , Francesca Piceci Sparascio 3 , Hossein Hozhabri 6 , Tommaso Mazza 7 , Maria Cristina Digilio 4 , Bruno Dallapiccola 4 , Marco Tartaglia 4 , Bruno Marino 5 , Jeroen den Hertog 8 , Alessandro De Luca 3
+ et al

[No authors listed]

Author information
  • 1 IRCCS Neuromed, Localita` Camerelle, 86077, Pozzilli, Italy.
  • 2 Hubrecht Institute-KNAW and University Medical Center Utrecht, 3584CT, Utrecht, The Netherlands.
  • 3 Molecular Genetics Unit, Casa Sollievo della Sofferenza Hospital, IRCCS, 71013, San Giovanni Rotondo, Italy.
  • 4 Genetics and Rare Diseases Research Division, Bambino Gesù Children Hospital, IRCCS, 00146, Rome, Italy.
  • 5 Division of Pediatric Cardiology, Department of Pediatrics, "Sapienza" University, 00161, Rome, Italy.
  • 6 Department of Experimental Medicine, Sapienza University of Rome, 00161, Rome, Italy.
  • 7 Bioinformatics Unit, Casa Sollievo della Sofferenza Hospital, IRCCS, 71013, San Giovanni Rotondo, Italy.
  • 8 Institute of Biology, 2300RC, Leiden, The Netherlands.

摘要


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 altered atrioventricular canal patterning, providing evidence of their functional relevance in vivo. Our findings support a role of defective NFATC1 function in the etiology of isolated and heterotaxy-related AVSD.

KEYWORDS: Atrioventricular septal defect, NFATC1, congenital heart defect, heterotaxy, oculo-auriculo-vertebral spectrum