Congenital heart disease affects approximately two out of every 100 newborns worldwide, making it one of the most common types of birth defects. However, scientists are still working to understand the exact reason why these heart abnormalities develop.
Researchers at the University of Copenhagen have now identified a previously unknown cellular mechanism that may provide an important part of the explanation.
“We have discovered a new communication system on the outside of the cell that is critical for the proper formation of the heart during embryonic development,” says Lars Allan Larsen, an expert in congenital heart disease and professor in the Department of Cellular and Molecular Medicine. “This discovery changes our understanding of why some congenital heart defects arise. You could say that we have identified an important cog in a very complex machine.”
A small cell antenna helps guide the heart’s growth
The newly identified mechanism operates within the primary cilium, a microscopic antenna-shaped structure that extends from the surface of most cells in the body.
Primary cilia help cells sense and interpret chemical signals from their surroundings. These signals can influence key cellular decisions, including whether a cell divides, moves, or dies.
The researchers found that three proteins, TAK1, TAB2, and PKA-Cα, act together as a signaling hub within this cellular antenna. Their activity appears to be important for the normal formation of the heart.
“These proteins act as molecular instructions that tell stem cells when and how to develop into heart muscle cells,” explains Soren Tvorup Christensen, professor of cell biology in the Department of Biology. “However, genetic changes can disrupt this communication, causing ‘antenna defects,’ which can lead to congenital heart defects.”
Congenital heart disease
Congenital heart disease refers to structural abnormalities of the heart that arise during fetal development.
Approximately 2.3 to 2.5 million newborns worldwide develop congenital heart disease each year. An estimated 16 million people have congenital heart disease (data from 2023). Together these numbers make congenital heart defects among the most common birth defects worldwide.
Some congenital heart defects occur as part of a broader genetic syndrome that can also produce abnormalities elsewhere in the body. These conditions are known as syndromic congenital heart diseases. When a baby develops a congenital heart defect without other complications, the condition is classified as non-syndromic congenital heart disease. The current study focuses on syndromic heart defects.
Sources: World Heart Federation and Danish Heart Foundation
Testing the mechanism in zebrafish and stem cells
To verify the system, the researchers combined genetic information from people with congenital heart defects with experiments involving zebrafish, human cells and mouse stem cells.
They began by studying the genetic data of several thousand patients with congenital heart defects. Researchers looked for rare mutations and compared how often certain genetic changes appeared in patients versus healthy individuals. Variants that appeared more frequently among patients were considered more likely to contribute to the condition.
The team then tested what these genetic changes actually do.
Using genetic engineering, the scientists recreated the same mutations in zebrafish and examined how they affected heart formation. The results showed that changes in these genes can interfere with normal heart development and reduce heart function in zebrafish.
The researchers also studied several types of cells in laboratory experiments. These tests allowed them to examine the signaling system in more detail and determine what happens when molecular communication pathways are disrupted.
Together, genetics and experimental patient findings pointed to primary ciliation as an important part of the process that may contribute to congenital heart defects.
“We investigate the mechanism from different angles and use 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 Alan Larsen.
What is the primary cilium?
The primary cilium is a microscopic antenna-like structure that emerges from the surface of most cells. Its main role is to help cells sense information from their surroundings.
It can detect a variety of signaling molecules, including hormones and growth factors, and convert those signals into instructions that direct cellular behavior. These messages can tell a cell when to divide, change its metabolism, produce new tissue, move, or die.
Primary cilia are found in almost all cell types and are particularly important during embryonic development. They help coordinate the formation of organs including the heart, brain and skeleton. Because of this broad role, problems with ciliary function can affect several organs at the same time.
Sources: Lars Alan Larsen and Søren Tvorup Christensen
The effects may extend beyond the heart
The researchers also found evidence that the mechanism may affect the development of organs other than the heart.
The rare mutations examined in the study were identified in people with so-called syndromic congenital heart disease. In these cases, the heart defect is part of a broader genetic syndrome that can also affect other parts of the body.
Experiments in zebrafish, along with detailed studies of cilia in other tissues, have suggested that the same cellular machinery may contribute to the development of many organs.
“When the ciliary mechanism fails, it usually affects the development of many other organs as well. This may explain why some patients with congenital heart disease also develop associated defects and conditions affecting the brain, kidneys and skeleton. The mechanism provides a unified explanation for diseases that we previously had difficulty understanding,” says Søren Tvorup Christensen.
Because problems with primary cilium are already known to be associated with several rare genetic disorders, the researchers believe the newly discovered mechanism could ultimately improve scientists’ understanding of a wide range of diseases.
“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 ultimately facilitate early identification of patients and the development of targeted therapies,” says Lars Alan Larsen.
About the study
The study investigates how a specific signaling pathway within the cells’ antennae, known as the primary cilium, affects heart development during embryonic development. The researchers combined genetic analyzes of patients with congenital heart defects with experiments involving zebrafish, mouse stem cells, and cellular models.
The results indicate that this signaling pathway contributes to the development of cardiomyocytes and proper formation of the heart during the embryonic stage.
Because the evidence comes primarily from genetic associations and experimental models, researchers cannot yet definitively determine how the mechanism works in humans. However, they say the combined results provide strong evidence that the same process is relevant to people.
The study has just been published in the scientific journal PLoS Biology.
Researchers from the University of Copenhagen who contributed to the study are: Søren Tvorup Christensen, Lars Alan Larsen, Canan Doganli, Oscar Capper-Thomsen, Daniel A. Baird, Yasmin Ali, Menachem V. K. Sarosi, Lyn Janet Jessen, Pauline Munk Trulsen, Johan Bye Mogensen, Maria Schröder Holm, Lorenzo Botto, Maria Diamanti, Jindřiška Leischner Fialová, and Lotte Bang Pedersen.
