Sponsored by the U.S. Department of Energy Human Genome Program
Human Genome News Archive Edition
Human Genome News, May 1993; 5(1)
An international research group composed of 6 teams of researchers affiliated with 11 institutions has identified the gene that causes Huntington's disease (HD). As reported in the March 26 issue of Cell, the Huntington's Disease Collaborative Research Group used cloned "trapped exons" to isolate the gene IT15. The collaborative group was formed after James Gusella's team at Massachusetts General Hospital (MGH) mapped the gene in 1983 to the distal portion of the short (p) arm of chromosome 4; it was one of the first uses of DNA marker technology for this purpose.
"The cooperative effort was important," said Gusella, whose laboratory also pinpointed the HD gene. "This has been a very, very hard mystery to solve. If the separate research teams had been competing rather than cooperating, the search would have gone on a lot longer." About a year before the gene was discovered, the MGH group took a considered risk in concentrating on one promising 500-kb segment while the rest of the consortium searched elsewhere in the region.
As in the case of fragile X syndrome and myotonic dystrophy, the HD mutation involves a polymorphic trinucleotide repeat, an unstable DNA segment in which the sequence is copied many more times than normal. This defect was found in all 75 HD families studied. In people without the disease the number of repeats ranges from 11 to 34; those affected by HD showed a minimum of 42, with an estimated 100 copies in a severely affected patient. Preliminary evidence indicates that the number of repeats may relate to the severity of the disease and the age at which it becomes apparent: the shorter the repeat, the older the individual when symptoms first appear; the longer the repeat, the earlier the onset of symptoms.
HD, a fatal progressive disease that attacks both mind and body by killing brain cells, is usually manifested by the age of 35 with small involuntary movements (chorea) that gradually overwhelm all parts of the body. HD is also characterized by cognitive decline leading to dementia and psychiatric manifestations. Both sexes are equally affected, and each offspring of an affected person has a 50% chance of inheriting the disease, for which no effective treatment is known. About 1 in 25,000 Americans carries the gene, and another 150,000 are at risk. Rare spontaneous mutations can also occur in individuals whose parents are not affected.
In addition to the MGH team, the Huntington's collaboration included groups led by Hans Lehrach of the Imperial Cancer Research Fund (U.K.); David Housman at Massachusetts Institute of Technology; John Wasmuth of the University of California, Irvine; Francis Collins at the University of Michigan at Ann Arbor; Peter Harper of the University of Wales College of Medicine (U.K.); and others. The work was supported by grants from NIH and a number of other foundations and institutions.
"The search for the Huntington's disease gene has been the most difficult gene hunt yet," said Collins. "Its success now means that accurate diagnosis of Huntington's disease will be available almost immediately, the basic biology of the disease can at last be understood, and the potential for new treatments can be vigorously pursued."
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The Human Genome Project (HGP) was an international 13-year effort, 1990 to 2003. Primary goals were to discover the complete set of human genes and make them accessible for further biological study, and determine the complete sequence of DNA bases in the human genome. See Timeline for more HGP history.
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