The most common cause of sudden death in young athletes a heart condition known as hypertrophic cardiomyopathy can develop from a single genetic mutation that disrupts at least two other genes, interfering with the normal beating of the heart, UCSF-led research suggests. All three genes encode contractile proteins that interact in heart muscle.
Hypertrophic cardiomyopathy affects one person in 500, and genetic defects are thought to be responsible for at least half of all cases. Although mutations in a gene for a contractile protein known as cardiac troponin T, or TNNT2 --have been identified in 15 percent of these cases, how the mutations cause disease has not been determined.
The genes function cant be easily explored by traditional knockout methods in mice, since this would kill the embryo as soon as the heart begins to develop. But another animal, the inch-long zebrafish, revealed the answers. Using radiation to create random mutations in the zebrafish genome and then tracking their impact in the embryo, the scientists discovered an embryo whose heart does not beat, which they dubbed silent heart.
With genetic techniques they found that the silent heart gene encodes the zebrafish counterpart of TNNT2. A lack of the protein in the embryos, they discovered, leads to reduced expression of two other contractile proteins, which like TNNT2 are necessary for formation of the sarcomere, the fundamental unit of heart contraction. The research shows for the first time that TNNT2 is essential for the heart to beat.
The finding leads to a new model of what might be going wrong in cardiac sudden death of young athletes. This little fish seems to have a lot to teach us, said Didier Stainier, PhD, UCSF associate professor of biochemistry and biophysics and senior author of a paper on the research in Nature Genetics.