Recently, mutations in the Kruppel-like factor 13 (KLF13) gene encoding a Kruppel-like transcription factor have been reported to cause congenital heart disease (CHD). However, due to pronounced genetic heterogeneity, the mutational spectrum of KLF13 in other cohorts of cases suffering from distinct types of CHD remain to be ascertained. In the present investigation, by Sanger sequencing of KLF13 in 316 unrelated cases affected by different forms of CHD, a new mutation in heterozygous status, NM_015995.3: c.430G>T; p.(Glu144*), was detected in an index patient affected with patent ductus arteriosus (PDA) and ventricular septal defect (VSD), as well as bicuspid aortic valve (BAV), with a mutation frequency of ~0.32%. Genetic investigation of the available family members of the proband demonstrated that the truncating mutation co-segregated with CHD. The nonsense mutation was not observed in 400 unrelated volunteers without CHD who were enrolled as control subjects. Quantitative biological measurements with dual luciferase reporters revealed that Glu144*-mutant KLF13 did not transactivate the downstream genes vascular endothelial growth factor A and natriuretic peptide A. In addition, the mutation abrogated the synergistic transcriptional activation between KLF13 and T-box transcription factor 5, a well-established CHD-causing gene. In conclusion, the present study indicates that genetically defective KLF13 contributes to familial PDA and VSD, as well as BAV, which expands the phenotypic spectrum linked to KLF13, and reveals a novel molecular pathogenesis of the disease, providing a new molecular target for the early prophylaxis and individualized treatment of CHD.
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.
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