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.
This finding changes our understanding of why some congenital heart defects arise.
“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 why some 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.
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.
Congenital heart disease is defined as a structural defect in the heart that develops during embryonic development.
Each year, approximately 2.3-2.5 million newborns are affected by congenital heart disease globally. 16 million people are estimated to be living with congenital heart disease (data from 2023). This makes congenital heart defects one of the most common birth defects.
Some heart defects are part of a genetic syndrome that may also cause other defects. These are known as syndromic congenital heart disease. When a child is born without other complications, the condition is referred to as a non-syndromic congenital heart disease. The researchers focus on syndromic heart defects in this study.
Sources: World Heart Federation and Danish Heart Foundation
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.
The researchers observed effects not only in the heart.
The primary cilium is a microscopic, antenna-like structure that extends from the surface of most cells in the body. It helps cells detect signals from their surroundings.
The cilium detects many different signaling molecules, including growth factors and hormones, and translates them into messages that instruct the cell on what to do. For example, it helps determine when a cell should divide, adjust its metabolism, form new tissue, move or die.
The primary cilium is present in almost all cell types and plays an important role during embryonic development, helping coordinate the formation of organs such as the heart, brain and skeleton. As a result, defects in ciliary function can affect multiple organs simultaneously.
Sources: Lars Allan Larsen and Søren Tvorup Christensen
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.
Read the study: “TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development”.