Sci. Aging Knowl. Environ., 9 July 2003
Vol. 2003, Issue 27, p. nw96
[DOI: 10.1126/sageke.2003.27.nw96]


Bad Seeds

Mutation that exacerbates Huntington's disease can appear even before sperm generation

Mitch Leslie;2003/27/nw96

Key Words: spermatid • spermatogonium • laser capture microdissection • polyglutamine disease

Men who carry the gene for Huntington's disease (HD) can leave a doubly grim legacy. Not only do they have a 50% chance of passing the killer gene to their children, but because of a genetic quirk, the kids inherit a more vicious form of the illness. According to a new study, mutations that worsen the severity of the disease occur at several stages of sperm formation, suggesting that the flaw can arise from multiple causes.

Always fatal, HD doesn't usually cause symptoms until after age 30. The scourge results from extra copies of the amino acid glutamine in a particular brain protein. People with fewer than 36 glutamines in a row are healthy, whereas those with 40 or more fall ill. Sperm from men with HD accumulate even longer versions of the troublesome stretch. The greater the number of glutamines, the earlier the disease erupts, so a man's affected children usually sicken and die younger than he did. Researchers don't know what causes lengthening or when it occurs. A study of one mouse model of the disease suggested that elongation came after cells in the testes had undergone meiosis, the process that halves chromosome number and yields sperm. However, Norman Arnheim, a molecular geneticist at the University of Southern California in Los Angeles, and colleagues found that sperm from men with HD carry a large number of expansion mutations. This observation implies that expansions probably occur before meiosis, they argued.

To check their hypothesis, the researchers isolated DNA from testicular cells of a man who had died from HD at age 48. They measured the length of the repeat-coding region and compared it with the same region in the man's blood cells. Nearly all of the blood cells carried between 49 and 51 repeats. However, the median number of repeats in testicular cells that had undergone meiosis was 87; a second group of cells that either had begun meiosis or were about to start carried 77. These findings suggest that expansion can occur before cells launch into meiosis. The second group's lower percentage of segments with more than 80 repeats also hints that lengthening continues during and possibly after meiosis. Results for another individual were similar. "Our data suggest that there may not be any single molecular mechanism responsible for all these expansions," says Arnheim.

Because expansion can precede meiosis, many other body cells--not just those destined to turn into sperm--should also exhibit elongated genes, says neurobiologist James Burke of Duke University Medical Center in Durham, North Carolina. But they don't, and neither do women's eggs, so a key question, he says, is "what occurs in pre-meiotic sperm cells that allows that genetic expansion that is not seen in other cells." Comparing the timing of extension in humans and in the multiple mouse models of the disease should help gauge how closely the rodents mimic the human illness, adds neurogeneticist Albert La Spada of the University of Washington, Seattle. Although pinning down the causes of expansion will be challenging, he says, further research might uncover why men pass on this unwelcome inheritance.

--Mitch Leslie

July 9, 2003
  1. S.-R. Yoon, L. Dubeau, N. S. Wexler, Venezuela Huntington Disease Project, N. Arnheim, Huntington disease expansion mutations in humans can occur before meiosis is completed. Proc. Natl. Acad. Sci. U.S.A., July 2003 [e-pub ahead of print]. [Abstract] [Full Text] [Links will work when the article goes online.]
Citation: M. Leslie, Bad Seeds. Sci. SAGE KE 2003, nw96 (9 July 2003);2003/27/nw96

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