GATA5 loss-of-function mutations underlie tetralogy of fallot

• Published in: International journal of medical sciences Vol. 10; no. 1; pp. 34 - 42
• Main Authors: Wei, Dong, Bao, Han, Liu, Xing-Yuan, Zhou, Ning, Wang, Qian, Li, Ruo-Gu, Xu, Ying-Jia, Yang, Yi-Qing
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher 01-01-2013
• Subjects: Adolescent; Adult; Alleles; Asian Continental Ancestry Group - genetics; Base Sequence; Child; Child, Preschool; Female; GATA5 Transcription Factor - genetics; Heterozygote; Humans; Infant; Male; Mutation; Pedigree; Polymorphism, Genetic; Research Paper; Sequence Alignment; Tetralogy of Fallot - genetics; Tetralogy of Fallot - mortality; Tetralogy of Fallot - physiopathology; Tetralogy of Fallot; GATA5; Genetics; Congenital heart disease; Transcription factor
• ISSN: 1449-1907; 1449-1907
• DOI: 10.7150/ijms.5270

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.