Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect
Ferese, Rosangela; Bonetti, Monica; Consoli, Federica; Guida, Valentina; Sarkozy, Anna; Lepri, Francesca Romana; Versacci, Paolo; Gambardella, Stefano; Calcagni, Giulio; Margiotti, Katia; Piceci Sparascio, Francesca; Hozhabri, Hossein; Mazza, Tommaso; Digilio, Maria Cristina; Dallapiccola, Bruno; Tartaglia, Marco; Marino, Bruno; Hertog, Jeroen den; De Luca, Alessandro
(2018) Human Mutation, volume 39, issue 10, pp. 1428 - 1441
(Article)
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
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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.
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Keywords: Atrioventricular septal defect, congenital heart defect, heterotaxy, NFATC1, oculo-auriculo-vertebral spectrum, Genetics, Genetics(clinical)
ISSN: 1059-7794
Publisher: Wiley-Liss Inc.
Note: Funding Information: The authors wish to thank the patients who participated in this research. Funding: This work was supported with grant support from the Italian Ministry of Health (RF 2010 2310935 and RC 2016 to A.D.L.), a grant from the Research Council for Earth and Life Sciences [ALW 819.02.021] with financial aid from the Netherlands Organisation for Scientific Research (NWO) (to J.d.H.), and Fondazione Bambino Gesù (CUoRE to M.T.). Funding Information: The authors wish to thank the patients who participated in this research. Funding: This work was supported with grant support from the Italian Ministry of Health (RF 2010 2310935 and RC 2016 to A.D.L.), a grant from the Research Council for Earth and Life Sciences [ALW 819.02.021] with financial aid from the Netherlands Organisation for Scientific Research (NWO) (to J.d.H.), and Fondazione Bambino Ges? (CUoRE to M.T.). Conception and design: R.F., A.S., J.d.H., A.D.L. Funding Information: Fondazione Bambino Gesù, Grant/Award Number: CUoRE; Italian Ministry of Health, Grant/Award Numbers: RF 2010 2310935, RC 2016; Research Council for Earth and Life Sciences with financial aid from the Netherlands Organisation for Scientific Research (NWO), Grant/Award Number: ALW 819.02.021 Jeroen den Hertog and Alessandro De Luca equally contributed as senior authors in this work. Publisher Copyright: © 2018 Wiley Periodicals, Inc.
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