Scientists uncover cellular mechanism behind congenital heart defects

Congenital heart disease affects approximately two in every 100 newborns globally. But why do they occur?

An important part of the answer may lie in a previously unknown mechanism on the surface of our cells. Researchers from the University of Copenhagen have identified this mechanism in a new study.

"We have discovered a new communication system on the exterior of the cell that is crucial for the proper formation of the heart during embryonic development. This finding changes our understanding of how congenital heart defects arise. You could say that we have identified an important cog in a highly complex machine," says Lars Allan Larsen, an expert in congenital heart disease and Professor at the Department of Cellular and Molecular Medicine.

The mechanism is located in the primary cilium, a microscopic 'antenna' that protrudes from most cells in the body. The cilium's role is to interpret the body's signaling molecules, enabling the cell to determine whether it should divide, move or die, for example.

In the study, the researchers show that three proteins, TAK1, TAB2 and PKA-Cα, function as a signaling hub within the cell's antenna and play a significant role in heart formation.

"These proteins act as molecular instructions that tell stem cells when and how to develop into heart muscle cells. However, genetic alterations can disrupt this communication, causing 'antenna defects', which may lead to congenital heart defects," explains Søren Tvorup Christensen, Professor of cell biology at the Department of Biology.

Zebrafish and mouse stem cells

In the study, the researchers combined genetic data from patients with experiments in zebrafish, human cells and mouse stem cells to understand how the mechanism works.

First, the researchers analyzed genetic data from several thousand people with congenital heart defects in search of rare mutations. They investigated whether specific genetic changes occurred more frequently in patients than in healthy individuals and therefore were likely to play a role in the disease.

Next, they examined the practical consequences of these mutations. Using genetic engineering, the researchers introduced the same genetic changes into zebrafish and observed their effects on heart development. The experiments showed that alterations in these genes can lead to defects and impaired heart function in zebrafish.

Finally, the researchers conducted experiments in various cell types in the laboratory to understand how the mechanism functions at the molecular level and what happens when the signaling pathways are disrupted.

The experiments, together with the genetic data from patients, pointed the researchers toward the mechanism in the primary cilium and thus to a possible explanation for the development of congenital heart defects.

"We investigate the mechanism from many different angles and using many different methods, all of which support what we observe in patients. Therefore, we are reasonably confident that this mechanism also exists in humans," says Lars Allan Larsen.

May be crucial for other diseases

The researchers observed effects not only in the heart.

In the study, the rare genetic mutations were identified in patients with so-called syndromic congenital heart disease. Syndromic heart defects are caused by an underlying genetic syndrome that often also leads to defects and associated conditions in other organs.

At the same time, experiments in zebrafish and detailed studies of cilia in other tissues suggested that the mechanism is also important for the development of other organs.

"When the ciliary mechanism fails, it typically affects the development of several other organs as well. This may explain why some patients with congenital heart disease also have defects and related conditions affecting the brain, kidneys and skeleton. The mechanism provides a unifying explanation for diseases that we have previously struggled to understand," says Søren Tvorup Christensen.

The researchers therefore believe that the discovery could help improve the understanding and treatment of a wide range of diseases caused by defects in the primary cilium.

"Many rare genetic diseases are caused by changes in genes that affect ciliary function, yet the underlying mechanisms have remained poorly understood. This new knowledge may eventually make it easier to identify patients early and develop targeted treatments," says Lars Allan Larsen.