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A Novel NKX2.6 Mutation Associated with Congenital Ventricular Septal Defect

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Abstract

Congenital heart disease (CHD) is the most common birth defect and is the most prevalent non-infectious cause of infant death. Aggregating evidence demonstrates that genetic defects are involved in the pathogenesis of CHD. However, CHD is genetically heterogeneous and the genetic determinants for CHD in an overwhelming majority of patients remain unknown. In this study, the coding regions and splice junctions of the NKX2.6 gene, which encodes a homeodomain transcription factor crucial for cardiovascular development, were sequenced in 210 unrelated CHD patients. As a result, a novel heterozygous NKX2.6 mutation, p.K152Q, was identified in an index patient with ventricular septal defect (VSD). Genetic analysis of the proband’s available family members showed that the mutation cosegregated with VSD transmitted as an autosomal dominant trait with complete penetrance. The missense mutation was absent in 400 control chromosomes and the altered amino acid was completely conserved evolutionarily across species. Due to unknown transcriptional targets of NKX2.6, the functional characteristics of the identified mutation at transcriptional activity were analyzed by using NKX2.5 as a surrogate. Alignment between human NKX2.6 and NKX2.5 proteins displayed that K152Q-mutant NKX2.6 was equivalent to K158Q-mutant NKX2.5, and introduction of K158Q into NKX2.5 significantly reduced its transcriptional activating function when compared with its wild-type counterpart. This study firstly links NKX2.6 loss-of-function mutation with increased susceptibility to isolated VSD, providing novel insight into the molecular mechanism underpinning VSD and contributing to the development of new preventive and therapeutic strategies for this common form of CHD.

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Acknowledgments

The authors are greatly thankful to the participants for their devotion to the study. This work was supported in part by Grants from the National Natural Science Fund of China (81270161 and 81271927), the Key Program for Basic Research of Shanghai, China (14JC1405500), the Experimental Animal Program of Shanghai, China (12140902800), the Fundamental Research Fund for Central University of Ministry of Education, China (15072), the Scientific Research Fund of Health Bureau, Shanghai, China (2010119), and the Excellent Discipline Leader Training Foundation of Pudong New Strict, Shanghai, China (PWRd2012-05).

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Authors and Affiliations

  1. Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai, 200065, China

    Juan Wang, Ke-Ke Ding & Wei-Jun Xu

  2. Department of Emergency Internal Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China

    Jian-Hui Mao

  3. Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China

    Xing-Yuan Liu

  4. Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China

    Xing-Biao Qiu, Ruo-Gu Li, Xin-Kai Qu & Ying-Jia Xu

  5. Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Ri-Tai Huang & Song Xue

  6. Departments of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China

    Yi-Qing Yang

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  1. Juan Wang
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Correspondence to Juan Wang or Yi-Qing Yang.

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Juan Wang, Jian-Hui Mao, and Ke-ke Ding have contributed equally to the work.

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Wang, J., Mao, JH., Ding, KK. et al. A Novel NKX2.6 Mutation Associated with Congenital Ventricular Septal Defect. Pediatr Cardiol 36, 646–656 (2015). https://doi.org/10.1007/s00246-014-1060-x

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