PUBLICATION
Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect
- Authors
- Ferese, R., Bonetti, M., Consoli, F., Guida, V., Sarkozy, A., Lepri, F.R., Versacci, P., Gambardella, S., Calcagni, G., Margiotti, K., Sparascio, F.P., Hozhabri, H., Mazza, T., Digilio, M.C., Dallapiccola, B., Tartaglia, M., Marino, B., Hertog, J.D., De Luca, A.
- ID
- ZDB-PUB-180715-5
- Date
- 2018
- Source
- Human Mutation 39(10): 1428-1441 (Journal)
- Registered Authors
- Keywords
- Congenital heart defect, NFATC1, atrioventricular septal defect, heterotaxy, oculo-auriculo-vertebral spectrum
- MeSH Terms
-
- Alleles
- Animals
- Chromosome Deletion
- Female
- Fluorescent Antibody Technique
- Gene Expression
- Genes, Reporter
- Genetic Association Studies*
- Genetic Predisposition to Disease*
- Heart Septal Defects/diagnosis
- Heart Septal Defects/genetics*
- Heterozygote*
- High-Throughput Nucleotide Sequencing
- Humans
- Male
- Mutation, Missense*
- NFATC Transcription Factors/genetics*
- NFATC Transcription Factors/metabolism
- Phenotype
- Sequence Analysis, DNA
- Zebrafish
- PubMed
- 30007050 Full text @ Hum. Mutat.
Citation
Ferese, R., Bonetti, M., Consoli, F., Guida, V., Sarkozy, A., Lepri, F.R., Versacci, P., Gambardella, S., Calcagni, G., Margiotti, K., Sparascio, F.P., 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.
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 first two 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. This article is protected by copyright. All rights reserved.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping