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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 ; Luca, Alessandro

Human mutation, 2018-10, Vol.39 (10), p.1428-1441 [Periódico revisado por pares]

United States: Hindawi Limited

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Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect
Autor: 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 ; Luca, Alessandro
Assuntos: Alleles ; Animals ; Atrioventricular septal defect ; Calcineurin ; Chromosome Deletion ; congenital heart defect ; Defects ; Down's syndrome ; Etiology ; Female ; Fluorescent Antibody Technique ; Gene Expression ; Genes, Reporter ; Genetic Association Studies ; Genetic Predisposition to Disease ; Heart ; Heart Septal Defects - diagnosis ; Heart Septal Defects - genetics ; heterotaxy ; Heterozygote ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; Missense mutation ; Mutation ; Mutation, Missense ; NF-AT protein ; NFATC Transcription Factors - genetics ; NFATC Transcription Factors - metabolism ; NFATC1 ; Nuclear transport ; oculo‐auriculo‐vertebral spectrum ; Phenotype ; Sequence Analysis, DNA ; Tbx1 protein ; Transcription ; Vertebrae ; Zebrafish
É parte de: Human mutation, 2018-10, Vol.39 (10), p.1428-1441
Notas: Communicated by Mark H. Paalman
Jeroen den Hertog and Alessandro De Luca equally contributed as senior authors in this work.
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SourceType-Scholarly Journals-1
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Descrição: 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. In this study, we report the identification of NFATC1 gene mutations in a small fraction of subjects with isolated and heterotaxy‐related atrioventricular septal defect. Functional characterization of NFATC1 mutants documented defective nuclear translocation and decreased transcriptional transactivation activity in vitro. When expressed in zebrafish, 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.
Editor: United States: Hindawi Limited
Idioma: Inglês

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Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect

United States: Hindawi Limited

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