Genetic mechanism behind congenital heart disease identified

London: Researchers have now offered new insights into the genetic roots of congenital heart disease, thus opening the door to developing potential therapies to fight this chronic and potentially fatal disorder.

Scientists at the Gladstone Institutes have identified a finely tuned mechanism by which foetal heart muscle develops into a healthy and fully formed beating heart.

Researchers in the laboratory of Gladstone Senior Investigator Benoit Bruneau, PhD, describe the roles that two genes—Ezh2 and Six1—play in embryonic heart development, while also uncovering how the genetic basis of embryonic heart formation can have profound health consequences later in life.

This research highlights the emerging importance of a biological process called “epigenetics,” in which a genetic change that is inherited by a cell or organism early during development has long-term consequences.

Epigenetics is of particular interest in heart development, as the incorrect activation of genes in foetal development can lead to congenital heart disease into adulthood.

At specific times during healthy heart development, Ezh2 acts as a “master regulator,” shutting off genes that are no longer needed or that need to be kept off. In the past, the focus has been on which genes get switched on during normal heart development.

But in this paper, Dr. Bruneau, along with Gladstone Postdoctoral Scholar Paul Delgado-Olguin, PhD, investigated which genes must remain off to ensure the development of a healthy heart.

In laboratory experiments, Drs. Bruneau and Delgado-Olguin removed Ezh2 from mice at various developmental stages, monitoring any ensuing genetic or physical changes and comparing them to mice whose Ezh2 remained intact.

Surprisingly, mice without Ezh2 developed normally in the uterus. It wasn``t until after birth that they began to show problems. Their hearts became enlarged and weakened and were unable to pump blood efficiently.

An enlarged heart is a hallmark feature of cardiomyopathy, a form of congenital heart disease that afflicts thousands of children each year and for which the only manifestation may be sudden death.

Further analysis revealed that Six1 is normally on only for a brief period during heart development, after which Ezh2 shuts it off for good. But without Ezh2 to act as a regulator, Six1 remains on—leading to heart problems later in life.

The study has been published online in Nature Genetics.


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