Int J Med Sci 2013; 10(1):34-42. doi:10.7150/ijms.5270

Research Paper

GATA5 loss-of-Function Mutations Underlie Tetralogy of Fallot

Dong Wei1#, Han Bao1#, Xing-Yuan Liu1✉, Ning Zhou1, Qian Wang2, Ruo-Gu Li2, Ying-Jia Xu2, Yi-Qing Yang2✉

1. Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China;
2. Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, 241 West Huaihai Road, Shanghai 200030, China.
# contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See for full terms and conditions.
Wei D, Bao H, Liu XY, Zhou N, Wang Q, Li RG, Xu YJ, Yang YQ. GATA5 loss-of-Function Mutations Underlie Tetralogy of Fallot. Int J Med Sci 2013; 10(1):34-42. doi:10.7150/ijms.5270. Available from

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Tetraology of Fallot (TOF) is the most common form of cyanotic congenital heart disease and is a major cause of significant morbidity and mortality. Emerging evidence demonstrates that genetic risk factors are involved in the pathogenesis of TOF. However, TOF is genetically heterogeneous and the genetic defects responsible for TOF remain largely unclear. In the present study, the whole coding region of the GATA5 gene, which encodes a zinc-finger transcription factor essential for cardiogenesis, was sequenced in 130 unrelated patients with TOF. The relatives of the index patients harboring the identified mutations and 200 unrelated control individuals were subsequently genotyped. The functional characteristics of the mutations were analyzed using a luciferase reporter assay system. As a result, 2 novel heterozygous GATA5 mutations, p.R187G and p.H207R, were identified in 2 families with autosomal dominantly inherited TOF, respectively. The variations were absent in 400 control alleles and the altered amino acids were completely conserved evolutionarily. Functional analysis showed that the GATA5 mutants were associated with significantly decreased transcriptional activation compared with their wild-type counterpart. To our knowledge, this is the first report on the association of GATA5 loss-of-function mutations with TOF, suggesting potential implications for the early prophylaxis and allele-specific therapy of human TOF.

Keywords: Congenital heart disease, Tetralogy of Fallot, Genetics, Transcription factor, GATA5.