Genetic analysis of the CITED2 gene promoter in isolated and sporadic congenital ventricular septal defects

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

doi:10.1111/jcmm.16218

Cited by 15 publications

(17 citation statements)

References 32 publications

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“…Genomic DNA was extracted from peripheral leukocytes using standard procedure (18). The sequence of the ISL1 promoter was obtained from the GenBank database (NCBI, NG_023040.1) and amplified from human genomic DNA.…”

Section: Sequence Analysismentioning

confidence: 99%

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

Zheng

Chen

Liu

et al. 2021

American Journal of Physiology-Cell Physiology

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Ventricular septal defects (VSD) are the most common congenital heart defects (CHD). Studies have documented that ISL1 has a crucial impact on cardiac growth, but the role of variants in the ISL1 gene promoter in patients with VSD has not been explored. In 400 subjects (200 isolated and sporadic VSD patients: 200 healthy controls), we investigated the ISL1 gene promoter variant and performed cellular functional experiments by using the dual-luciferase reporter assay to verify the impact on gene expression. In the ISL1 promoter, 5 variants were found only in VSD patients by sequencing. Cellular functional experiments demonstrated that three variants decreased the transcriptional activity of the ISL1 promoter (P < 0.05). Further analysis with the online JASPAR database demonstrated that a cluster of putative binding sites for transcription factors may be altered by these variants, possibly resulting in change of ISL1 protein expression and VSD formation. Our study has for the first time identified novel variants in the ISL1 gene promoter region in the Han Chinese patients with isolated and sporadic VSD. Additionally, the cellular functional experiments, electrophoretic mobility shift assay, and bioinformatic analysis have demonstrated that these variants significantly alter the expression of the ISL1 gene and affect the binding of transcription factors, likely resulting in VSD. Therefore, this study may provide new insights into the role of the gene promoter region for a better understanding of genetic basis of the formation of CHD and may promote further investigations on mechanism of the formation of CHD.

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Section: Sequence Analysismentioning

confidence: 99%

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

Zheng

Chen

Liu

et al. 2021

American Journal of Physiology-Cell Physiology

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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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“…In humans, variants in CITED2 were identified in patients with congenital heart defects (CHD) such as sinus venosus atrial septal defects, abnormal pulmonary venous return to the right atria, Tetralogy of Fallot, dextrocardia and other ventricular septal defects [ 41 , 43 ], also seen in patients with MYRF variants [ 44 ]. More importantly, several of these variants are localized in the promoter region of CITED2 and have been proven to alter CITED2 transcriptional activity, decreasing their expression [ 41 , 45 ]. Therefore, it is possible that haploinsufficiency of transcription factors of CITED2 , such as MYRF , can influence its expression levels and lead to heart defects.…”

Section: Discussionmentioning

confidence: 99%

MYRF: A New Regulator of Cardiac and Early Gonadal Development—Insights from Single Cell RNA Sequencing Analysis

Calonga‐Solís

Fabbri‐Scallet

Ott

et al. 2022

JCM

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De novo variants in the myelin regulatory factor (MYRF), a transcription factor involved in the differentiation of oligodendrocytes, have been linked recently to the cardiac and urogenital syndrome, while familiar variants are associated with nanophthalmos. Here, we report for the first time on a patient with a de novo stop-gain variant in MYRF (p.Q838*) associated with Scimitar syndrome, 46,XY partial gonadal dysgenesis (GD) and severe hyperopia. Since variants in MYRF have been described in both 46,XX and 46,XY GD, we assumed a role of MYRF in the early development of the bipotential gonad. We used publicly available single cell sequencing data of human testis and ovary from different developmental stages and analysed them for MYRF expression. We identified MYRF expression in the subset of coelomic epithelial cells at stages of gonadal ridge development in 46,XX and 46,XY individuals. Differential gene expression analysis revealed significantly upregulated genes. Within these, we identified CITED2 as a gene containing a MYRF binding site. It has been shown that Cited2−/− mice have gonadal defects in both testis and ovary differentiation, as well as defects in heart development and establishment of the left–right axis. This makes MYRF a potential candidate as an early regulator of gonadal and heart development via upregulation of the transcriptional cofactor CITED2.

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Genetic analysis of the CITED2 gene promoter in isolated and sporadic congenital ventricular septal defects

Cited by 15 publications

References 32 publications

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

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

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

MYRF: A New Regulator of Cardiac and Early Gonadal Development—Insights from Single Cell RNA Sequencing Analysis

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