Oct. 4, 1997 Bar Harbor -- Researchers at The Jackson Laboratory have identified the gene that is defective in a new mouse model known as "slow-wave epilepsy," or swe. This is the first genetic model to exhibit both petit mal (absence) and grand mal (convulsive) seizures, and promises to be the most authentic model yet for petit mal epilepsy in humans.
Epilepsy is a neurological disorder of recurrent partial or generalized seizures estimated to affect one percent of the U.S. population, or three million people. Absence seizures primarily occur in children and are characterized by brief lapses in consciousness during which the person appears to be staring into space. The child does not fall and recovery is prompt. Convulsive seizures are more severe, typically lasting from 1 to 7 minutes, and involve loss of consciousness and motor control. The person falls and the body goes rigid, with jerking and twitching of extremities.
Although the complex mechanisms of epilepsy are still a mystery, the seizures are known to result from the misfiring of neurons in the brain. Instead of transmitting electrical impulses in an orderly manner, epileptic neurons fire all at once, creating a "storm" that disrupts normal brain function. Half of all human epilepsies are estimated to have a genetic basis, but only a few genes are known at this time.
The new development in epilepsy research is reported in the Oct. 3, 1997, issue of the journal Cell by a team led by Jackson Laboratory Staff Scientist Wayne Frankel and postdoctoral fellow Gregory Cox. They find that swe mice have a defect in Nhe1, a gene encoding a cell membrane ion transporter that has been studied extensively in many rodent and human cell types for its "housekeeping" role in regulating pH and cell volume.
"Slow-wave epilepsy mice have a bad transporter, due to a mutation that occurred naturally in the Lab's large breeding colonies," says Dr. Frankel. "The gene is there, but it is dead." Nhe1 is unrelated to the first absence epilepsy gene discovered, which occurred in a Jackson Laboratory mouse called tottering as reported in Cell on Nov. 15,1996. That discovery was made jointly with a research team from the National Cancer Institute Frederick Cancer Research and Development Center in Maryland.
The brain-specific abnormality of swe mice was a surprise because Nhe1 is expressed in so many different cell types. Dr. Frankel says the vulnerability of a few brain cells to changes in pH is likely to underlie the epilepsy. Co-author Dr. Jeffrey Noebels of Baylor College of Medicine, who has been analyzing brain waves in epileptic Jackson Lab mice for years, found that the electrical storm pattern in swe petit mal seizures is most similar to that of human absence epilepsy, and that the mice seem to outgrow it, also typical of humans. The swe mice also exhibit grand mal seizures and a stumbling gait, or ataxia, which is the characteristic that led to their identification by alert animal caretakers. "This is a unique mouse, with more essential elements of human absence epilepsy than any existing mouse model," says Dr. Frankel. "It will be exciting to see how much more we can learn about human absence epilepsy by studying swe mice."
Co-authors with Drs. Frankel, Cox, and Noebels on the Cell paper are geneticists Cathleen Lutz and Audrey Fu of The Jackson Laboratory; pathologist Roderick Bronson of Tufts University School of Medicine; and Nhe experts Peter Aronson, Daniel Biemesderfer, and Chao-Ling Yang of Yale University School of Medicine.
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