Genetics

CLEVER METHOD: Roger K. Wolff of Progenitor Inc. led a research team that used linkage disequilibrium mapping to locate the gene for hereditary hemochromatosis. J.N. Feder, A. Gnirke, W. Thomas, Z. Tsuchihashi, D.A. Ruddy, A. Basava, F. Dormishian, R. Domingo, M.C. Ellis, A. Fullan, L.M. Hinton, N.L. Jones, B.E. Kimmel, G.S. Kronmal, P. Lauer, V.K. Lee, D.B. Loeb, F.A. Mapa, E. McClelland, N.C. Meyer, G.A. Mintier, N. Moeller, T. Moore, E. Morikang, C.E. Prass, L. Quintana, S.M. Starnes, R.C. Schatzman, K.J. Brunke, D.T. Drayna, N.J. Risch, B.R. Bacon, R.K. Wolff, "A novel MHC class-I-like gene is mutated in patients with hereditary hemochromatosis," Nature Genetics, 13:399-408, 1996. (Cited more than 236 times since publication) Comments by Roger K. Wolff, vice president of genetics, Progenitor Inc., Menlo Park, Calif. The conventional method of identifying a mutant gene's locale is by analyzing linkage, the relationship between genes on the same chromosome that causes them to be inherited together. In linkage analysis, genetic markers are used to define a stretch of DNA carrying a disease gene that runs in a family. This linkage area tends to become smaller through the generations, as the chromosome carrying the mutation continually recombines with normal chromosomes. In some instances, a single mutation in a gene will cause a large proportion of the disease. This occurs when a mutation is introduced into the population and persists, even though the original, founding individual has become lost in history. For geneticists, the result is "linkage disequilibrium." A response to this situation is to examine the gene pool of an entire population as if it were an extended family. Such studies are usually done in places where isolated populations live. But in the research conducted for this paper, an outbred or nonisolated population was used: 178 patients collected from 32 clinical centers across the United States, who had in common only that they were all Caucasian and they all suffered from the iron metabolism disorder called hereditary hemochromatosis. "It's a very common predisposition, occurring in about one in 200 individuals, and it has very serious health implications," notes the paper's senior author, Roger K. Wolff. His team at Mercator Genetics Inc. of Menlo Park, Calif.--which has since been acquired by Progenitor Inc., also of Menlo Park--collaborated on this research with scientists at Stanford University School of Medicine and St. Louis University School of Medicine. The effects of hemochromatosis frequently appear in mid-adulthood, primarily among people of Northern European descent, usually after decades of excessive iron accumulation in various organs including the pancreas, liver, and heart. If untreated, patients can suffer from conditions such as diabetes, cirrhosis, liver cancer, and cardiac dysfunction, often culminating in early death. The ancient practice of phlebotomy, or regular blood-letting, is an effective treatment if the condition is diagnosed early. "Our approach was to get all the DNA from this region." - Roger Wolff In the 1970s, French researchers first mapped the gene for hemochromatosis to the vicinity of the human lymphocyte antigen (HLA) region on the short arm of chromosome 6. Wolff and colleagues aimed to more precisely define this region by identifying in unrelated patients the segment of chromosome 6 that had remained the most conserved, or genetically unchanged, through the generations. "Our approach was to get all the DNA from this region," explains Wolff. Extending their search far beyond the limits of two previously identified markers, the researchers identified a 250- kilobase region more than three megabases away from HLA. They used multiple approaches to identify genes, including sequencing the entire region, and isolated 15 genes from it. One gene contained two missense alterations, one of which the researchers found was homozygous in 83 percent of their patients. The gene encoded a novel protein significantly similar in amino acid composition to the major histocompatablity complex (MHC) class-I proteins of HLA. They had discovered their culprit, now known as HFE. "Our biology group here has since shown that the second variant in this gene also has the ability to affect iron regulation," Wolff reports. In March, Progenitor researchers published results of work showing that the other mutation of HFE interferes with the gene's ability to interact with the receptor of the iron-binding protein transferrin (J.N. Feder et al., Proceedings of the National Academy of Sciences, 95:1472-7, 1998). A year ago, the American Medical Association adopted an official directive urging routine screening for hemochromatosis. This paper enabled the development of a now widely used DNA-based test for early detection.

Genetics

The Scientist Staff

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