Abstract 11371: Comprehensive Genetic Approach for Congenital Heart Disease Revealed Sequence Variants in Genes Encoding Cardiac Transcription Factors
Congenital heart defects (CHD) occur in nearly 1% of all live births and are the major cause of infant mortality and morbidity. Although the underlying genetic etiology of CHD, especially the non-syndromic phenotype, is largely unknown, recent advances in molecular genetics using animal models have suggested several candidate genes that may cause various CHD. In order to explore genetic causes of human OFT defect, we screened mutations of candidate genes using DNA extracted from immortalized cell-lines of patients with non-syndromic persistent truncus arteriosus. Recently, we reported mutationsin GATA6, and clarified that GATA6 mutant proteins lost their transcriptional activity and failed to regulate semaphorin 3C and plexin A2, and eventually, were responsible for OFT defect (Kodo et al. PNAS). Next, we analyzed further DNA samples that were collected from immortalized cell-lines and original genomes of 519 patients with various non-syndromic CHD. We selected genes that encode transcription factors essential for cardiac development, NKX2.5, GATA4, GATA6, TBX1, MEF2C and ISL1, and identified eight sequence variants in four genes (NKX2.5: A6V; GATA4: T330R, S339R; GATA6: E142K, 247-250insGGGA, A255T, 323insH; MEF2C: A103V) in nine individuals. All of sequence variants were confirmed by analyses of patients’ original genomes and were not found in 500 control population without CHD. Most mutant proteins showed significant changes in transcriptional activities for the NPPA and other promoters that function during the heart development, as well as decreased synergistic activity with other transcriptional factors. These findings suggest that the disturbance of regulatory circuit of these cardiac transcription factors may cause a subset of non-syndromic CHD.
- © 2010 by American Heart Association, Inc.