Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect

Rosangela Ferese; Monica Bonetti; Federica Consoli; Valentina Guida; Anna Sarkozy; Francesca Romana Lepri; Paolo Versacci; Stefano Gambardella; Giulio Calcagni; Katia Margiotti; Francesca Piceci Sparascio; Hossein Hozhabri; Tommaso Mazza; Maria Cristina Digilio; Bruno Dallapiccola; Marco Tartaglia; Bruno Marino; Jeroen den Hertog; Alessandro De Luca

doi:10.1002/humu.23593

Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect

Rosangela Ferese, Monica Bonetti, Federica Consoli, Valentina Guida, Anna Sarkozy, Francesca Romana Lepri, Paolo Versacci, Stefano Gambardella, Giulio Calcagni, Katia Margiotti, Francesca Piceci Sparascio, Hossein Hozhabri, Tommaso Mazza, Maria Cristina Digilio, Bruno Dallapiccola, Marco Tartaglia, Bruno Marino, Jeroen den Hertog, Alessandro De Luca

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

18 Citaten (Scopus)

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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.

Originele taal-2	Engels
Pagina's (van-tot)	1428-1441
Aantal pagina's	14
Tijdschrift	Human Mutation
Volume	39
Nummer van het tijdschrift	10
DOI's	https://doi.org/10.1002/humu.23593
Status	Gepubliceerd - okt. 2018

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10.1002/humu.23593

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Ferese, R., Bonetti, M., Consoli, F., Guida, V., Sarkozy, A., Lepri, F. R., Versacci, P., Gambardella, S., Calcagni, G., Margiotti, K., Piceci Sparascio, F., Hozhabri, H., Mazza, T., Digilio, M. C., Dallapiccola, B., Tartaglia, M., Marino, B., Hertog, J. D., & De Luca, A. (2018). Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect. Human Mutation, 39(10), 1428-1441. https://doi.org/10.1002/humu.23593

@article{fcd495402cca491bb4874f5436f5fbaf,

title = "Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect",

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 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.",

author = "Rosangela Ferese and Monica Bonetti and Federica Consoli and Valentina Guida and Anna Sarkozy and Lepri, {Francesca Romana} and Paolo Versacci and Stefano Gambardella and Giulio Calcagni and Katia Margiotti and {Piceci Sparascio}, Francesca and Hossein Hozhabri and Tommaso Mazza and Digilio, {Maria Cristina} and Bruno Dallapiccola and Marco Tartaglia and Bruno Marino and Hertog, {Jeroen den} and {De Luca}, Alessandro",

note = "{\textcopyright} 2018 Wiley Periodicals, Inc.",

year = "2018",

month = oct,

doi = "10.1002/humu.23593",

language = "English",

volume = "39",

pages = "1428--1441",

journal = "Human Mutation",

issn = "1059-7794",

publisher = "Wiley-Liss Inc.",

number = "10",

}

Ferese, R, Bonetti, M, Consoli, F, Guida, V, Sarkozy, A, Lepri, FR, Versacci, P, Gambardella, S, Calcagni, G, Margiotti, K, Piceci Sparascio, F, Hozhabri, H, Mazza, T, Digilio, MC, Dallapiccola, B, Tartaglia, M, Marino, B, Hertog, JD & De Luca, A 2018, 'Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect', Human Mutation, vol. 39, nr. 10, blz. 1428-1441. https://doi.org/10.1002/humu.23593

TY - JOUR

T1 - Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect

AU - Ferese, Rosangela

AU - Bonetti, Monica

AU - Consoli, Federica

AU - Guida, Valentina

AU - Sarkozy, Anna

AU - Lepri, Francesca Romana

AU - Versacci, Paolo

AU - Gambardella, Stefano

AU - Calcagni, Giulio

AU - Margiotti, Katia

AU - Piceci Sparascio, Francesca

AU - Hozhabri, Hossein

AU - Mazza, Tommaso

AU - Digilio, Maria Cristina

AU - Dallapiccola, Bruno

AU - Tartaglia, Marco

AU - Marino, Bruno

AU - Hertog, Jeroen den

AU - De Luca, Alessandro

PY - 2018/10

Y1 - 2018/10

N2 - 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.

AB - 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.

U2 - 10.1002/humu.23593

DO - 10.1002/humu.23593

M3 - Article

C2 - 30007050

SN - 1059-7794

VL - 39

SP - 1428

EP - 1441

JO - Human Mutation

JF - Human Mutation

IS - 10

ER -

Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect

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