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Tracking the cause of Huntington's disease
In mice with a human mutation, gender of embryo contributes to instability
Edward R. Winstead

Most individuals with Huntington's disease have an unstable and repetitive stretch of DNA on chromosome 4. The stretch—three letters of genetic code known as a CAG triplet repeat—can expand, and this expansion is believed to be the underlying mutation in the disease. Other inherited neurodegenerative disorders and the most common form of inherited mental retardation, fragile X syndrome, involve similar DNA expansions.

‘This mutation is sensitive, and it knows the gender of the embryo’

The precise moment when the expansion occurs is unknown. Another unknown is why males and females are affected disproportionately by some of these diseases. To investigate both phenomena, researchers at the Mayo Clinic and Foundation, in Minnesota, bred male mice that have a portion of the human gene involved in Huntington's disease (HD) with normal female mice. Like humans, mice transmit expansions predominantly through the male. The number of CAG repeats in the mutant HD gene of the fathers was established prior to mating the animals.

The experiment yielded dozens of offspring and an interesting result: Male and female progeny had CAG repeats in their HD genes that were of different lengths. In general, male offspring expanded the repeat, while female offspring contracted the repeat.

"We were amazed by this result," says Cynthia T. McMurray, who led the study. The researchers tried but could not explain the differences between the genders by a parental gene mechanism—something originating with the contributing parent. Instead, they concluded that the expansions and contractions took place early in embryonic development. "Something in the embryo is contributing to this expansion," says McMurray.

"This mutation is sensitive, and it knows the gender of the embryo," she continues. "And the sex chromosomes are the only way the mutation could know the difference between genders." She hypothesizes that coded factors on the sex chromosomes somehow talk to the mutation.

This hypothesis challenges some assumptions about genomic imprinting, the notion that a gene behaves one way when inherited from the father and another way when inherited from the mother. There certainly are good examples of parent-of-origin effects on gene expression, says McMurray. But parents may not be the whole story in all cases. "Because the Huntington's expansion occurs beyond the point at which the parent controls the changes," she says, "another set of information has to be involved."

The researchers are conducting experiments to try to explain how chromosomal factors might influence expansion in the embryo. The rationale for the mouse study was to identify the point at which expansion occurs in the hope that this would facilitate the development of therapeutic interventions. The research appeared in a recent issue of Human Molecular Genetics.

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Kovtun, V.I., Therneau, T.M., and McMurray, C.T. Gender of the embryo contributes to CAG instability in transgenic mice containing a Huntington's disease gene. Hum Mol Genet 9, 2767-2775 (November 1, 2000).

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