Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect
| Autor: | Maria Cristina Digilio, Hossein Hozhabri, Marco Tartaglia, Stefano Gambardella, Monica Bonetti, Tommaso Mazza, Anna Sarkozy, Valentina Guida, Federica Consoli, Jeroen den Hertog, Paolo Versacci, Katia Margiotti, Francesca Piceci Sparascio, Bruno Dallapiccola, Alessandro De Luca, Bruno Marino, Francesca Romana Lepri, Rosangela Ferese, Giulio Calcagni |
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| Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine TBX1 Heterozygote Down syndrome Atrioventricular septal defect Mutation Missense Fluorescent Antibody Technique Gene Expression 030105 genetics & heredity Biology Gene mutation congenital heart defect 03 medical and health sciences Genes Reporter medicine Genetics Animals Humans Missense mutation Genetic Predisposition to Disease Genetics(clinical) Atrioventricular Septal Defect Alleles Genetic Association Studies Zebrafish Genetics (clinical) atrioventricular septal defect heterotaxy NFATC1 oculo-auriculo-vertebral spectrum genetics NFATC Transcription Factors Heart Septal Defects High-Throughput Nucleotide Sequencing NFAT Sequence Analysis DNA medicine.disease Phenotype 030104 developmental biology Atrioventricular canal Female Chromosome Deletion Heterotaxy |
| Zdroj: | Human Mutation, 39(10), 1428. Wiley-Liss Inc. Human Mutation, 39(10), 1428-1441. Wiley-Liss Inc. |
| ISSN: | 1059-7794 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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