NR2F2 lossoffunction mutation is responsible for congenital bicuspid aortic valve.
Int J Mol Med
; 43(4): 1839-1846, 2019 Apr.
Article
em En
| MEDLINE
| ID: mdl-30720060
ABSTRACT
Congenital bicuspid aortic valve (BAV) represents the most common type of cardiac birth defect affecting 0.42% of the general population, and accounts for a markedly increased incidence of lifethreatening complications, including valvulopathy and aortopathy. Accumulating evidence has demonstrated the genetic basis of BAV. However, the genetic basis for BAV in the majority of cases remains to be elucidated. In the present study, the coding regions and splicing donors/acceptors of the nuclear receptor subfamily 2 group F member 2 (NR2F2) gene, which encodes a transcription factor essential for proper cardiovascular development, were sequenced in 176 unrelated cases of congenital BAV. The available family members of the proband carrying an identified NR2F2 mutation and 280 unrelated, sex and ethnicitymatched healthy individuals as controls were additionally genotyped for NR2F2. The functional effect of the mutation was characterized using a dualluciferase reporter assay system. As a result, a novel heterozygous NR2F2 mutation, NM_021005.3 c.288C>A; p.(Cys96*), was identified in a family with BAV, which was transmitted in an autosomal dominant mode with complete penetrance. The nonsense mutation was absent from the 560 control chromosomes. Functional analysis identified that the mutant NR2F2 protein had no transcriptional activity. Furthermore, the mutation disrupted the synergistic transcriptional activation between NR2F2 and transcription factor GATA4, another transcription factor that is associated with BAV. These findings suggested NR2F2 as a novel susceptibility gene of human BAV, which reveals a novel molecular pathogenesis underpinning BAV.
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Base de dados:
MEDLINE
Assunto principal:
Valva Aórtica
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Fator II de Transcrição COUP
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Mutação com Perda de Função
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Cardiopatias Congênitas
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article