1. NR2F2 loss‑of‑function mutation is responsible for congenital bicuspid aortic valve
- Author
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Ying‑Jia Xu, Ri‑Tai Huang, Ruo‑Gu Li, Ruo‑Min Di, Xing‑Biao Qiu, Juan Wang, Song Xue, Min Zhang, Qi Qiao, Pradhan Abhinav, Xiu‑Mei Li, and Yi-Qing Yang
- Subjects
Heart Defects, Congenital ,Male ,Transcriptional Activation ,0301 basic medicine ,Proband ,Mutant ,Nonsense mutation ,Population ,Heart Valve Diseases ,Biology ,Cell Line ,COUP Transcription Factor II ,03 medical and health sciences ,0302 clinical medicine ,Bicuspid aortic valve ,Bicuspid Aortic Valve Disease ,Loss of Function Mutation ,Genetics ,medicine ,Humans ,education ,Gene ,education.field_of_study ,Base Sequence ,General Medicine ,Middle Aged ,medicine.disease ,Penetrance ,GATA4 Transcription Factor ,Phenotype ,030104 developmental biology ,Aortic Valve ,030220 oncology & carcinogenesis ,embryonic structures ,Mutation (genetic algorithm) ,Female ,Mutant Proteins - Abstract
Congenital bicuspid aortic valve (BAV) represents the most common type of cardiac birth defect affecting 0.4‑2% of the general population, and accounts for a markedly increased incidence of life‑threatening 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 ethnicity‑matched healthy individuals as controls were additionally genotyped for NR2F2. The functional effect of the mutation was characterized using a dual‑luciferase 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 GATA‑4, 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.
- Published
- 2019