Congenital heart disease affects roughly two out of every 100 newborns worldwide, making it one of the most common types of birth defects. Yet scientists are still working to understand exactly 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 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.
A Tiny Cellular Antenna Helps Guide Heart Development
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. Those signals can influence major cellular decisions, including whether a cell divides, moves or dies.
The researchers found that three proteins, TAK1, TAB2 and PKA-Cα, work together as a signaling hub inside 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. 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.
Congenital Heart Disease
Congenital heart disease refers to structural abnormalities of the heart that arise during embryonic development.
Approximately 2.3 to 2.5 million newborns worldwide are affected by congenital heart disease each year. An estimated 16 million people are living with congenital heart disease (data from 2023). Together, these figures make congenital heart defects among the most common birth defects worldwide.
Some congenital heart defects occur as part of a wider genetic syndrome that can also produce abnormalities elsewhere in the body. These cases are known as syndromic congenital heart disease. When a child has 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 investigate 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 genetic data from several thousand patients with congenital heart defects. The researchers searched for rare mutations and compared how often particular 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 those 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 greater detail and determine what happens when its molecular communication pathways are disrupted.
Together, the patient genetics and experimental findings pointed to the primary cilium as an important part of the process that may contribute to 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.
What Is the Primary Cilium?
The primary cilium is a microscopic antenna-like structure that projects 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 guide 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 nearly every type of cell and are especially important during embryonic development. They help coordinate the formation of organs including the heart, brain, and skeleton. Because of this widespread role, problems with ciliary function can affect several organs at the same time.
Sources: Lars Allan Larsen and Søren Tvorup Christensen
The Effects May Extend Beyond the Heart
The researchers also found evidence that the mechanism may influence 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, a 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, suggested that the same cellular mechanism may contribute to the development of several 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.
Because problems involving the primary cilium are already known to be associated with many rare genetic disorders, the researchers believe the newly discovered mechanism could ultimately improve scientists’ understanding of a much wider 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 eventually make it easier to identify patients early and develop targeted treatments,” says Lars Allan Larsen.
About the Study
The study examines how a particular signaling pathway within the cells’ antennae, known as the primary cilium, affects heart development during embryonic development. The researchers combined genetic analyses of patients with congenital heart defects with experiments involving zebrafish, mouse stem cells, and cellular models.
The findings suggest that this signaling pathway contributes to the development of heart muscle cells and to proper heart formation during the embryonic stage.
Because the evidence comes primarily from genetic associations and experimental models, the researchers cannot yet definitively establish exactly how the mechanism operates in humans. However, they say the combined findings provide strong evidence that the same process is relevant in people.
The study has just been published in the scientific journal PLOS Biology.
Researchers from the University of Copenhagen who contributed to the study include: Søren Tvorup Christensen, Lars Allan Larsen, Canan Doganli, Oskar Kaaber Thomsen, Daniel A. Baird, Yeasmeen Ali, Menachem V. K. Sarusie, Line Jeanett Jessen, Pauline Munck Truelsen, Johanne Bay Mogensen, Maria Schrøder Holm, Lorenzo Buttò, Maria Diamanti, Jindřiška Leischner Fialová and Lotte Bang Pedersen.
