Identification of variants of <i>ISL1</i> gene promoter and cellular functions in isolated ventricular septal defects

Zheng, Siming; Chen, Huanxin; Liu, Xiaocheng; Yang, Qin; He, Guo‐Wei

doi:10.1152/ajpcell.00167.2021

Cited by 12 publications

(15 citation statements)

References 40 publications

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“…The promoter is a component of a gene that controls the onset and extent of gene expression, playing a key role in transcriptional regulation. Recently, studies have demonstrated that variants within the promoter region of a gene may be correlated to changes in gene expression levels, leading to disease (de Vooght et al, 2009; Juge et al, 2018; Zheng et al, 2021a; Zheng et al, 2021b).…”

Section: Introductionmentioning

confidence: 99%

Functional significance of novel variants of the MEF2C gene promoter in congenital ventricular septal defects

Zeng

Chen

Liu

et al. 2022

American J of Med Genetics Pt A

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Ventricular septal defect (VSD) is the most common congenital heart disease.Although the coding region of MEF2C is highly relevant to cardiac malformations, the role of MEF2C gene promoter variants in VSD patients has not been genetically investigated. We investigated the role of MEF2C gene promoter variants in 400 Han Chinese subjects (200 patients with isolated and sporadic VSD and 200 healthy controls). The promoter region of the MEF2C gene was sequenced that identified 10 variants. Expression vectors encompassing the variants and the firefly luciferase reporter gene plasmid (pGL3-basic) were constructed and subsequently transfected into HEK-293 cells. The luciferase activities were measured by Dual-luciferase reporter assay system. MEF2C gene promoter transcriptional activity was significantly reduced in 4 of the 10 variants in HEK-293 cells (P < 0.05). In addition, the JASPAR database was used to perform bioinformatics analysis, which showed that these variants disrupt the putative binding sites of transcription factors and affected the expression of MEF2C protein. This study for the first time identified the variants in the promoter of the MEF2C gene in Han Chinese population and revealed the role of these variants in the formation of VSD.

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Section: Introductionmentioning

confidence: 99%

Functional significance of novel variants of the MEF2C gene promoter in congenital ventricular septal defects

Zeng

Chen

Liu

et al. 2022

American J of Med Genetics Pt A

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“…Recent studies have shown that genetic polymorphisms in MYH6 are associated with risk of VSD [ 17 , 18 , 30 ]. Further, there is growing evidence that variants in the gene promoter play a key role in cardiac transcriptional regulation [ 19 – 21 , 31 , 32 ]. Based on the STRING database and a previous study [ 33 ], we found that the major proteins interacting with MYH6 protein are basically involved in myocardial development.…”

Section: Discussionmentioning

confidence: 99%

Identification and functional analysis of variants of MYH6 gene promoter in isolated ventricular septal defects

et al. 2022

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Background Ventricular septal defect is the most common form of congenital heart diseases. MYH6 gene has a critical effect on the growth and development of the heart but the variants in the promoter of MYH6 is unknown. Patients and methods In 604 of the subjects (311 isolated and sporadic ventricular septal defect patients and 293 healthy controls), DNA was extracted from blood samples and MYH6 gene promoter region variants were analyzed by sequencing. Further functional verification was performed by cellular experiments using dual luciferase reporter gene analysis, electrophoretic mobility shift assays, and bioinformatics analysis. Results Nine variants were identified in the MYH6 gene promoter and two of those variants [g.4085G>C(rs1222539675) and g.4716G>A(rs377648095)] were only found in the ventricular septal defect patients. Cellular function experiments showed that these two variants reduced the transcriptional activity of the MYH6 gene promoter (p < 0.001). Further analysis with online JASPAR database suggests that these variants may alter a set of putative transcription factor binding sites that possibly lead to changes in myosin subunit expression and ventricular septal defect formation. Conclusions Our study for the first time identifies variants in the promoter region of the MYH6 gene in Chinese patients with isolated and sporadic ventricular septal defect. These variants significantly reduced MYH6 gene expression and affected transcription factor binding sites and therefore are pathogenic. The present study provides new insights in the role of the MYH6 gene promoter region to better understand the genetic basis of VSD formation.

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“…As we have reported [ 19 , 20 ], genomic DNA was extracted from the peripheral blood of each subject using a blood genomic DNA extraction kit. Primers were designed according to the CITED2 reference sequence (NCBI: NG_016169.1).…”

Section: Methodsmentioning

confidence: 99%

Pathophysiological Role of Variants of the Promoter Region of CITED2 Gene in Sporadic Tetralogy of Fallot Patients with Cellular Function Verification

Chen

Hou

et al. 2022

Biomolecules

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Tetralogy of Fallot (TOF) is a common congenital heart malformation. Genetic variants in the CITED2 coding region are known to be significantly associated with cardiac malformation, but the role of variants in the CITED2 promoter region in the development of TOF remains unclear. In this study, we investigated CITED2 promoter variants in the DNA of 605 subjects, including 312 TOF patients and 293 unrelated healthy controls, by Sanger sequencing. We identified nine CITED2 gene promoter variants (including one novel heterozygous variant). Six were found only in patients with TOF and none in the control group. The transcriptional activity of the CITED2 gene promoter in mouse cardiomyocyte (HL-1) cells was significantly altered by the six variants (p < 0.05). The results of the electrophoretic mobility change assay and JASPAR database analysis showed that these variants generated or destroyed a series of possible transcription factor binding sites, resulting in changes in the CITED2 protein expression. We conclude that CITED2 promoter variants in TOF patients affect transcriptional activity and may be involved in the occurrence and progression of TOF. These findings may provide new insights into molecular pathogenesis and potential therapeutic insights in patients with TOF.

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Identification of variants of ISL1 gene promoter and cellular functions in isolated ventricular septal defects

Cited by 12 publications

References 40 publications

Functional significance of novel variants of the MEF2C gene promoter in congenital ventricular septal defects

Functional significance of novel variants of the MEF2C gene promoter in congenital ventricular septal defects

Identification and functional analysis of variants of MYH6 gene promoter in isolated ventricular septal defects

Pathophysiological Role of Variants of the Promoter Region of CITED2 Gene in Sporadic Tetralogy of Fallot Patients with Cellular Function Verification

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