For young athletes, the leading cause of sudden death is a heart disease known as hypertrophic cardiomyopathy, which affects one in 500 people. New research suggests the condition can develop from a single genetic mutation that halts production of its associated protein and disrupts the manufacture of two additional proteins. The findings, published online today by the journal Nature, illustrate for the first time that the protein cardiac troponin T (Tnnt2) is essential for a beating heart.
Genetic defects are thought to be responsible for half of all cases of hypertrophic cardiomyopathy and previous research had identified mutations in the TNNT2 gene in 15 percent of these occurrences. How these mutations caused the disease, however, remained unknown. In the new work, Amy J. Sehnert of the University of California, San Francisco, and colleagues turned to a unique source to investigate TNNT2's role in the often-fatal heart condition. The researchers utilized radiation to create random mutations in the genes of the inch-long zebrafish and monitored the embryos for abnormalities. For an embryo whose heart did not beat, the scientists determined that the affected gene encoded the zebrafish equivalent of Tnnt2. The team determined that a lack of either TNNT2 or Tnnt2 leads to reduced expression of two other proteins that are crucial to the development of the sarcomere--an essential unit of heart contraction. "Our research demonstrates the key importance of TNNT2 in the sarcomere and shows, surprisingly, that its expression can affect the expression of two other proteins," Sehnert says.
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Though the zebrafish can shed light on the causes of human disease, it does not serve as a perfect model. Whereas a zebrafish can continue to develop for nearly a week without the genes necessary for the heart muscle to contract, a human embryo lacking both copies of TNNT2 would not survive. Instead, sufferers of genetic forms of hypertrophic cardiomyopathy most likely have one normal and one mutated copy of the gene. According to study co-author Didier Stainier of the University of California, San Francisco, the finding could lead "to a new model of what might be going wrong in cardiac sudden death of young athletes."