During pregnancy, a series of intricate processes takes place for the heart to form correctly. Cells develop, proliferate, migrate, and die frequently, as the heart tissue transforms from a primary heart tube to four cardiac chambers. Scientists suspect that if there is a genetic mishap, those steps may not occur at the right time or place, resulting in congenital heart defects (CHDs).
One in 125 babies in the U.S. is not born with a perfect heart. CHDs are the most common major birth defects, and they range from simple to complex. For example, a heart defect called ventricular septal defect (VSD) involves an opening in the dividing wall between the two lower chambers of the heart. The hole allows an extra volume of blood to be pumped into the lungs, creating increased pressure, stress, and congestion.
Researchers at The Children’s Hospital of Philadelphia are searching for genes that could be linked to the presence of heart defects, and they recently reported on mutations in the gene NTRK3 that may be involved in the development of VSDs. NTRK3 regulates cell survival and encodes a protein called neurotrophic tyrosine kinase receptor C (TrkC).
“Finding the potential variations that are involved in heart defects in children is like finding a needle in a haystack, but you’re looking at a field of hundreds of haystacks,” said Petra Werner, DVM, PhD, a senior research associate in the laboratory of Elizabeth Goldmuntz, MD, professor of pediatrics in the Division of Cardiology at CHOP. “We picked NTRK3 as a candidate gene because deletion of this gene in mice will result in heart defects, and we had identified a patient with a VSD that had a large deletion encompassing NTRK3.”
In an article published in the December issue of Human Mutation, Dr. Werner and colleagues described how they screened 467 patients with related heart defects for NTRK3 mutations. They identified four of those patients with VSDs who had a missense mutation, which means an amino acid substitution occurred in the TrkC protein made by the gene that may modify how it works.
Next, the study team conducted experiments to see if the mutated TrkC lost any function. As a receptor, TrkC sits on cells’ membranes and waits for a signal from its ligand, a protein called neurotrophin-3 (NT-3). The results showed that one of the mutations significantly reduced TrkC’s ability to respond to the ligand, and subsequently TrkC failed to activate essential downstream signaling pathways.
In addition, the investigators found that cells expressing mutant TrkC showed altered cell growth. Usually, when NT-3 is present and binds to TrkC, it is a survival signal for the cell to differentiate and migrate. When the NT-3 ligand is absent, the cell begins to die, a process known as apoptosis. The experiments showed that cells with some of the mutant TrkC kept growing, even when they lacked NT-3.
“These results suggest that these mutations might permit increased cell growth under developmental conditions where morphologic changes require cell death,” the investigators wrote in the Human Mutation article.
Dr. Werner and her colleagues hypothesize that if TrkC’s function is impaired and allows the wrong heart cells to differentiate and migrate, then flaws could occur during the rapid remodeling of embryonic heart development.
“They may end up in the wrong location in the heart and be missed in other locations, resulting in malformations or holes,” Dr. Werner said. “But much more research must be done before we fully understand all of TrkC’s functions.”