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A Novel MEF2C Loss-of-Function Mutation Associated with Congenital Double Outlet Right Ventricle

Pediatric Cardiology volume 39, pages 794–804 (2018)Cite this article

Abstract

Congenital heart defect (CHD) represents the most prevalent birth defect, and accounts for substantial morbidity and mortality in humans. Aggregating evidence demonstrates the genetic basis for CHD. However, CHD is a heterogeneous disease, and the genetic determinants underlying CHD in most patients remain unknown. In the present study, a cohort of 186 unrelated cases with CHD and 300 unrelated control individuals were recruited. The coding exons and flanking introns of the MEF2C gene, which encodes a transcription factor crucial for proper cardiovascular development, were sequenced in all study participants. The functional effect of an identified MEF2C mutation was characterized using a dual-luciferase reporter assay system. As a result, a novel heterozygous MEF2C mutation, p.R15C, was detected in an index patient with congenital double outlet right ventricle (DORV) as well as ventricular septal defect. Analysis of the proband’s pedigree showed that the mutation co-segregated with CHD with complete penetrance. The missense mutation, which changed the evolutionarily conserved amino acid, was absent in 300 control individuals. Functional deciphers revealed that the mutant MEF2C protein had a significantly decreased transcriptional activity. Furthermore, the mutation significantly reduced the synergistic activation between MEF2C and GATA4, another transcription factor linked to CHD. This study firstly associates MEF2C loss-of-function mutation with DORV in humans, which provides novel insight into the molecular pathogenesis of CHD, suggesting potential implications for genetic counseling and personalized treatment of CHD patients.

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Acknowledgements

We sincerely thank the study subjects for their dedication to the research. This work was financially supported by grants from the National Natural Science Foundation of China (81470372) and the Natural Science Foundation of Shanghai, China (16ZR1432500).

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Author notes

  1. Cai-Xia lu, Wei Wang, and Qian Wang have contributed equally to the work.

Affiliations

  1. Department of Pediatrics, Huashan Hospital North, Fudan University, Shanghai, 201907, China

    Cai-Xia Lu

  2. Department of Parasitology, School of Basic Medical Science, Anhui Medical University, Hefei, 230032, Anhui, China

    Wei Wang

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

    Qian Wang & Xing-Yuan Liu

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

    Yi-Qing Yang

  5. Department of Cardiovascular Research Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China

    Yi-Qing Yang

  6. Department of Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China

    Yi-Qing Yang

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  1. Cai-Xia Lu
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  2. Wei Wang
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Lu, CX., Wang, W., Wang, Q. et al. A Novel MEF2C Loss-of-Function Mutation Associated with Congenital Double Outlet Right Ventricle. Pediatr Cardiol 39, 794–804 (2018). https://doi.org/10.1007/s00246-018-1822-y

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  • DOI: https://doi.org/10.1007/s00246-018-1822-y

Keywords

  • Congenital heart disease
  • Double outlet right ventricle
  • Genetics
  • Transcription factor
  • MEF2C
  • Reporter gene assay