Congenital heart disease affects approximately two in every 100 newborns globally, and researchers from the University of Copenhagen announced on Aug. 4 that they have identified a previously unknown mechanism on the surface of cells that may explain why these defects occur.
Lars Allan Larsen, Professor at the Department of Cellular and Molecular Medicine, said, "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."
The study found that this mechanism is located in the primary cilium—a microscopic antenna protruding from most cells—which interprets signaling molecules to help determine cell behavior such as division or movement. Researchers showed that three proteins—TAK1, TAB2, and PKA-Cα—act as a signaling hub within this structure and play an important role in heart formation.
Søren Tvorup Christensen, Professor of cell biology at the Department of Biology, said, "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." The research combined genetic data from patients with laboratory experiments using zebrafish models as well as human and mouse stem cells to observe how specific mutations impact development.
The study further indicated that rare genetic mutations affecting this mechanism were found not only in patients with syndromic congenital heart disease but also correlated with additional organ issues beyond just cardiac problems. Christensen said, "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." Larsen added that many rare genetic diseases are caused by gene changes impacting ciliary function: "This new knowledge may eventually make it easier to identify patients early and develop targeted treatments."
