Abstract
BVES is a transmembrane protein, our previous work demonstrated that single nucleotide mutations of BVES in tetralogy of fallot (TOF) patients cause a downregulation of BVES transcription. However, the relationship between BVES and the pathogenesis of TOF has not been determined. Here we reported our research results about the relationship between BVES and the right ventricular outflow tract (RVOT) stenosis. BVES expression was significantly downregulated in most TOF samples compared with controls. The expression of the second heart field (SHF) regulatory network genes, including NKX2.5, GATA4 and HAND2, was also decreased in the TOF samples. In zebrafish, bves knockdown resulted in looping defects and ventricular outflow tract (VOT) stenosis, which was mostly rescued by injecting bves mRNA. bves knockdown in zebrafish also decreased the expression of SHF genes, such as nkx2.5, gata4 and hand2, consistent with the TOF samples` results. The dual-fluorescence reporter system analysis showed that BVES positively regulated the transcriptional activity of GATA4, NKX2.5 and HAND2 promoters. In zebrafish, nkx2.5 mRNA partially rescued VOT stenosis caused by bves knockdown. These results indicate that BVES downregulation may be associated with RVOT stenosis of non-syndromic TOF, and bves is probably involved in the development of VOT in zebrafish.
Highlights
BVES is a transmembrane protein, our previous work demonstrated that single nucleotide mutations of BVES in tetralogy of fallot (TOF) patients cause a downregulation of BVES transcription
The expression pattern of BVES in right ventricular outflow tract (RVOT) tissues with TOF was examined by qRT-PCR, and 79 of the 83 cases were valid for qRT-PCR analysis
Our previous report showed that BVES allelic variants are associated with RVOT stenosis in TOF patients, which leads to the downregulation of BVES itself at the transcriptional and protein levels in the tissues of cases of RVOT stenosis with TOF containing allelic variants[38,39]
Summary
BVES is a transmembrane protein, our previous work demonstrated that single nucleotide mutations of BVES in tetralogy of fallot (TOF) patients cause a downregulation of BVES transcription. We reported our research results about the relationship between BVES and the right ventricular outflow tract (RVOT) stenosis. Bves knockdown in zebrafish decreased the expression of SHF genes, such as nkx2.5, gata[4] and hand[2], consistent with the TOF samplesresults. The knockout or knockdown of SHF regulatory network genes, such as Gata[414], nkx2.512,15, Tbx[116], Tbx2017, and Hand[218], leads to abnormal development of the outflow tract. Functional mutations of SHF genes, such as NKX2.519–21, TBX122,23, GATA424,25, TBX2026, and HAND227, were found in TOF patients The expression of these genes, including NKX2.528, GATA428, and TBX129, was significantly decreased in the cardiac tissue samples of TOF, indicating that the downregulation of SHF genes is associated with outflow tract stenosis
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