Scholarlink

Objective <p>This study aimed to investigate the potential role of TBX20 gene variants in the molecular pathogenesis of congenital ventricular septal defect (VSD) in pediatric patients.</p> Methods <p>Genetic sequencing and variant detection were performed for the TBX20 gene, a T-box transcription factor, in a cohort of 150 pediatric patients diagnosed with VSD, recruited from the Department of Cardiothoracic Surgery at Shanxi Children's Hospital. Functional characterization of newly identified variants was conducted using homology-based protein structural modeling, dual-luciferase reporter assays, and quantitative real-time polymerase chain reaction (qRT-PCR).</p> Results <p>Two variants within the highly conserved T-box DNA-binding domain were identified in five children: a synonymous variant c.576C &gt; T (p.Thr192Thr) and a missense variant c.577G &gt; A (p.Gly193Ser). Structural modeling predicted that the p.Gly193Ser substitution destabilized the TBX20 protein by altering its conformation and increasing its potential energy state. Functional assays demonstrated that this variant reduced TBX20 mRNA expression and significantly attenuated transactivation of the downstream target gene <i>ANF</i>. Bioinformatic analysis supported the deleterious functional impact of the p.Gly193Ser variant and its potential contribution to VSD pathogenesis. In contrast, the synonymous p.Thr192Thr variant was associated with increased transcriptional activity of TBX20 and enhanced regulation of <i>ANF</i>. qRT-PCR data indicated significantly reduced TBX20-G193S mRNA levels compared to wild-type (WT) when expressed independently (<i>p</i> &lt; 0.01), but elevated levels in the presence of GATA4 and NKX2-5 (<i>p</i> &lt; 0.001). Despite this, ANF transactivation remained significantly lower than WT, suggesting impaired functional capacity. These alterations may influence translational efficiency and contribute to abnormal cardiac septation.</p> Conclusion <p>The findings underscore the involvement of TBX20 gene variants in the etiology of pediatric VSD and provide mechanistic insights that may inform future clinical research and the development of targeted therapeutic strategies.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Structural and functional assessment of TBX20 gene variants in pediatric ventricular septal defect

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月4日

查看全文
  • Zhenzhen Qin,
  • Caixia Liu,
  • Jie Wang,
  • Yanmei Jin

摘要

Objective

This study aimed to investigate the potential role of TBX20 gene variants in the molecular pathogenesis of congenital ventricular septal defect (VSD) in pediatric patients.

Methods

Genetic sequencing and variant detection were performed for the TBX20 gene, a T-box transcription factor, in a cohort of 150 pediatric patients diagnosed with VSD, recruited from the Department of Cardiothoracic Surgery at Shanxi Children's Hospital. Functional characterization of newly identified variants was conducted using homology-based protein structural modeling, dual-luciferase reporter assays, and quantitative real-time polymerase chain reaction (qRT-PCR).

Results

Two variants within the highly conserved T-box DNA-binding domain were identified in five children: a synonymous variant c.576C > T (p.Thr192Thr) and a missense variant c.577G > A (p.Gly193Ser). Structural modeling predicted that the p.Gly193Ser substitution destabilized the TBX20 protein by altering its conformation and increasing its potential energy state. Functional assays demonstrated that this variant reduced TBX20 mRNA expression and significantly attenuated transactivation of the downstream target gene ANF. Bioinformatic analysis supported the deleterious functional impact of the p.Gly193Ser variant and its potential contribution to VSD pathogenesis. In contrast, the synonymous p.Thr192Thr variant was associated with increased transcriptional activity of TBX20 and enhanced regulation of ANF. qRT-PCR data indicated significantly reduced TBX20-G193S mRNA levels compared to wild-type (WT) when expressed independently (p < 0.01), but elevated levels in the presence of GATA4 and NKX2-5 (p < 0.001). Despite this, ANF transactivation remained significantly lower than WT, suggesting impaired functional capacity. These alterations may influence translational efficiency and contribute to abnormal cardiac septation.

Conclusion

The findings underscore the involvement of TBX20 gene variants in the etiology of pediatric VSD and provide mechanistic insights that may inform future clinical research and the development of targeted therapeutic strategies.