Human Genetics

Edited by: Karen Young Kreeger J.R. Burke, M.S. Wingfield, K.E. Lewis, A.D. Roses, J.E. Lee, C. Hulette, M.A. Pericak-Vance, J.M. Vance, "The Haw River Syndrome: Dentatorubropallidoluysian atrophy (DRPLA) in an African-American family," Nature Genetics, 7:521-4, 1994. (Cited in nearly 60 publications as of June 1996) Comments by James R. Burke and Jeffery M. Vance, Duke University Medical Center Many discoveries in the study of human genetic diseases come from reproductively isolated populations. Haw River syndrome, a neurodegenerative disorder, is one such example. The disease has affected five generations of an African American family living near the Haw River, a rural part of central North Carolina. A SMALL WORLD: Haw River syndrome in North Carolina and DRPLA in Japan are remarkably similar, says James Burke. The disorder is characterized by a mutation on chromosome 12 that causes neuronal loss in several parts of the brain. "Haw River syndrome is a slowly progressive neurodegenerative disease that begins with ataxia, or unsteadiness in movement," notes James R. Burke, an assistant professor of medicine at the Duke University Medical Center. "Frequently associated with the disease are psychiatric symptoms like those seen in schizophrenia. This is followed by chorea, or abnormal jerking movements, as seen in Huntington's disease." The syndrome has many neuropathological and clinical symptoms in common with Huntington's, spinocerebellar ataxia, and dentatorubropallidoluysian atrophy (DRPLA), a disease found almost exclusively in Japan. Despite these similarities, Haw River syndrome is sufficiently unique to be considered a new disease (T.W. Farmer et al., Archives of Neurology, 46:774-9, 1989), according to the authors. "In 1994 we began to look for the mutation that causes Haw River syndrome," says Burke. "At the same time, two groups of investigators, working independently-one led by Shoji Tsuji at Niigata University in Niigata, Japan, and another by Masao Yamada at the National Children's Medical Research Center in Tokyo-were working on the cause of DRPLA in Japan. They found the mutation and, because of the similarities of Haw River syndrome to DRPLA, we tested for linkage to the DRPLA region on chromosome 12 and found it. We then confirmed that the same mutation was present in individuals with Haw River syndrome and DRPLA." The mutation responsible for the disease is an expansion of the region on the DRPLA protein that encodes for the amino acid glutamine. "In the normal instructions for the DRPLA protein, there are 10 to 20 glutamines in a row, but people with the disease have at least 40 in a row," explains Burke. "It's this expansion that's responsible for the phenotype of the neurodegenerative disease, but we still don't know the function of the protein." "The history of the family is one of the most interesting features," remarks Jeffery M. Vance, an associate professor of medicine at Duke. "Here's a single, large family in rural North Carolina with an inherited neurodegenerative disease, and their disease ends up being caused by the same mutation that causes DRPLA, a disease that was rarely reported outside of Japan." Burke says that studies such as these highlight recent advances in neurogenetics, a factor that contributes to the paper's high number of citations. "We can now take single families with diseases that have been unknown and test them as new genes become discovered. Identification of the molecular defect responsible for disease allows us to diagnose a disease earlier, which will hopefully lead to treatment, or at least allow individuals to make informed decisions about having children." Burke, Vance, and colleagues are continuing to try to uncover the mechanism of the disease. "We recently published a paper in Nature Medicine [J.R. Burke et al., 2:347-50, 1996] on in vitro binding of the DRPLA protein," reports Burke. "We hypothesized that the polyglutamine portion of the protein is responsible for toxicity and that toxicity is mediated by protein-protein interactions. To test this idea, we identified brain proteins that bind to synthetic polyglutamine peptides. One protein we found was glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a critical protein involved in glycolysis." Glycolysis is involved in energy metabolism, and mistakes in this intricate process have been suspect for years in terms of a possible cause of Huntington's disease. The paper is dedicated to the memory of Martha Wingfield, a neurologist who worked at the John Umstead Hospital in Burner N.C., notes Burke. She died in 1993 of emphysema. "It was her curiosity and perseverance [that] provided us with the raw data and samples which allowed us to find the mutation that causes the disease," relates Vance.

Human Genetics

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