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Genetic analysis of the TBX1 gene promoter in ventricular septal defects

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Abstract

Congenital heart disease (CHD) is the most common birth defects in humans. The genetic causes for CHD remain largely unknown. T-box transcription factor 1 (TBX1), a dosage-sensitive regulator, plays a critical role in the heart development. Mutations in the coding regions of TBX1 gene have been associated to 22q11 deletion syndrome with cardiac defects and isolated CHD cases, including ventricular septal defect (VSD). To date, TBX1 gene promoter region has not been analyzed and reported in CHD patients. We hypothesized that the sequence variants within TBX1 gene promoter region may change TBX1 levels and mediate CHD development. In this study, the promoter regions of TBX1 gene were genetically and functionally analyzed in 280 VSD patients and 267 healthy controls. Two novel heterozygous variants, g.4353C>T and g.4510A>C, were found in two VSD patients, but in none of controls. The single-nucleotide polymorphism-rs41260844, g.4199T>C, was found more frequent in VSD patients than controls (P < 0.01). Functional analyses revealed that these sequence variants significantly enhanced transcriptional activities of TBX1 gene promoter. Therefore, the sequence variants within TBX1 gene promoter may contribute to the VSD etiology by altering the expression levels of TBX1 gene. Pharmaceutical or genetic manipulation of TBX1 gene expression may provide a novel personalized therapy to prevent and treat late cardiac complications for the adult CHD patients carrying these variants.

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Acknowledgments

This study was supported by National Natural Science Foundation of China (81070173) and Shandong Provincial Natural Science Foundation (ZR2010HM111).

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Authors and Affiliations

  1. Shandong Provincial Key Laboratory of Cardiac Disease Diagnosis and Treatment, Jining Medical University Affiliated Hospital, Jining Medical University, 79 Guhuai Road, Jining, 272029, Shandong, China

    Haihua Wang, Liming Ma, Haihong Meng, Yumei Liu, Shuchao Pang & Bo Yan

  2. Division of Ultrasound Medicine, Jining Medical University Affiliated Hospital, Jining Medical University, Jining, 272029, Shandong, China

    Dongfeng Chen & Wen Xie

Authors
  1. Haihua Wang
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  2. Dongfeng Chen
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  3. Liming Ma
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  4. Haihong Meng
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  5. Yumei Liu
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  6. Wen Xie
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  7. Shuchao Pang
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  8. Bo Yan
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Corresponding author

Correspondence to Bo Yan.

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Haihua Wang, Dongfeng Chen, and Liming Ma contributed equally to this work.

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Wang, H., Chen, D., Ma, L. et al. Genetic analysis of the TBX1 gene promoter in ventricular septal defects. Mol Cell Biochem 370, 53–58 (2012). https://doi.org/10.1007/s11010-012-1397-5

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  • DOI: https://doi.org/10.1007/s11010-012-1397-5

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