
A human heart. Image credit: Servier Medical Art (CC BY 4.0)
Congenital heart disease results in babies being born with structural defects to their hearts. It is one of the most common kind of human birth defects, yet its genetic causes remain poorly understood. Previous studies have identified a gene known as GATA6, which is sometimes altered in patients with the condition. As for most human genes, cells typically carry two GATA6 copies, each inherited from one parent. In many congenital heart disease patients, only one of the two copies of the gene presents harmful mutations. However, it has so far remained difficult to investigate in the laboratory how this genetic profile results in heart defects.
To bypass these limitations, Bisson et al. used human stem cells derived from the early embryo (known as hESCs) that can become any tissue in the body, including the heart. The team genetically designed hESC lines carrying either one (heterozygous) or two (homozygous) mutant copies of GATA6. Experiments showed that homozygous cells failed to generate any cardiac cells, while those stemming from heterozygous cells were partially impaired. Further molecular analyses established that GATA6 acts early in development by regulating WNT and BMP, two signaling pathways that contribute to hESCs becoming heart cells.
These findings indicate that embryos in which both copies of GATA6 are defective cannot generate heart cells, and therefore are not viable. They also suggest that modulating WNT and BMP pathways early during development may partially rescue heart defects in mutant embryos. Overall, the work by Bisson et al. offers a promising avenue for future research into congenital heart disease by providing researchers with hESC lines in which GATA6 is mutated.