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Stargazer gene provides new clues to calcium channel defects in absence epilepsy

IOWA CITY, Iowa -- Researchers have identified the gene for the epilepsy mouse mutation "stargazer" and report that the novel gene, which makes a protein named stargazin, produces a defect in a neuronal calcium channel in mice that may play a key role in absence epilepsy.

Kevin Campbell, Ph.D., University of Iowa College of Medicine professor of physiology and biophysics, and neurology, and Howard Hughes Medical Institute investigator, together with a team from the Jackson Laboratory, published this finding in the August issue of the scientific journal Nature Genetics.

The gamma subunit of the calcium channel, critical for proper function of the channel, was first identified by Campbell in 1990 as reported in the journal Science.

"As far as we knew at the time, the gene was only expressed in skeletal muscle, but we were looking for it in the brain." Campbell said. "The gene the Jackson Laboratory researchers found in the stargazer mouse model of epilepsy resembled the gamma subunit we had described." Together Campbell and the Jackson Laboratory team, led by Drs. Verity Letts and Wayne Frankel, identified the stargazer gene.

"This finding provides additional evidence that calcium channels are a key player in the initiation of epilepsy," said Campbell. "A future research goal will be to determine whether this gene is responsible for certain types of epilepsy in humans." Campbell hopes that the finding may someday provide the basis for a new drug therapy for the disease.

Epilepsy is a neurological disorder that affects approximately one percent of the U.S. population and has two major forms: absence (petit mal) and convulsive (grand mal). Absence seizures primarily occur in children and are characterized by brief lapses in consciousness during which the person appears to be staring into space. Convulsive seizures are more severe, typically lasting from one to seven minutes, and involve loss of consciousness and motor control.

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, Frankel said.

Stargazer, first described in 1990, arose spontaneously in the mouse colonies at the Jackson Laboratory and was detected for its distinctive head-tossing motion and unsteady gait. Stargazer mice have "spike-wave" seizures characteristic of absence epilepsy, with accompanying defects in the cerebellum and inner ear. The seizures last on average six seconds and recur more than 100 times an hour.

Calcium channels are a diverse family of proteins that are critical to the proper flow and release of chemicals known as neurotransmitters between nerve cells in the brain and to protein signaling within the cell. The structure of the calcium channel is very complex, comprising four "subunits," each with a number of different forms. The main subunit is alpha 1; the other subunits are regulatory in function and are called beta, alpha2/delta, and gamma.

In normal operation, the calcium channel "funnels" calcium ions to the nerve to trigger the release of neurotransmitters. In stargazer mice, the defective channel appears to allow excessive amounts of calcium ions to flow into the nerve, which leads to abnormal firing of neurons.

The gene, called Cacng2, represents the first evidence that calcium channels in the brain have a gamma subunit, and the first connection between gamma subunit function and calcium channel defects in absence epilepsy.

Ricardo Felix and Gloria Biddlecome, postdoctoral fellows working with Campbell, also contributed to this work.

The research was supported by grants from the National Institutes of Health, the Howard Hughes Medical Institute, the March of Dimes Birth Defects Foundation, and the National Cancer Institute.