Louis Kunkel, PhD, director of Children's Program in Genomics, achieved an early landmark of molecular genetics in 1986 when he identified dystrophin as the gene and protein altered in Duchenne muscular dystrophy, an inherited disease causing severe muscle weakness. In humans, mutations in the large dystrophin gene cause almost 90 percent of cases. Now, the geneticist has bred dystrophin-deficient zebrafish—with some surprising results.
Zebrafish, like humans, rely on dystrophin for normal muscle development. Kunkel's dystrophin-deficient fish are nearly immobile, and their muscles tear as they try to swim. Within five to seven days, most of them die. But perplexingly, in a small percentage, muscles regenerate and the fish survive to adulthood. "At around 15 days, the fish look normal," says Kunkel. "Somehow they've compensated."
He speculates that another gene is being turned on or up-regulated in the surviving fish to make up for the absent dystrophin. By looking at the gene expression in those fish, he hopes to identify a gene or genes that could be targeted to treat muscular dystrophy. So far, he has detected a few possible candidates.
Kunkel is also screening 3,000 known drug compounds by testing them on the affected zebrafish, hoping to find some that might counter dystrophin's absence and help the fishes' muscles develop normally. "If any molecule increases the survival rate of those fish, it may potentially be correcting for dystrophin deficiency," he says.