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Gene Discovery Provides Insights Into Epilepsy

A faulty conduit into nerve cells that causes them to fire uncontrollably appears to trigger the brief seizures present in some forms of absence, or petit mal, epilepsy, say investigators from the Howard Hughes Medical Institute at the University of Iowa College of Medicine and their colleagues at The Jackson Laboratory.

In research performed on the mutant "stargazer" strain of mice that serves as a model for absence epilepsy, HHMI investigator Kevin P. Campbell and collaborators Verity A. Letts and Wayne N. Frankel of The Jackson Laboratory have traced the seizures to a mutation in a gene called Cacng2, which codes for part of the "gate" that controls the flow of calcium into brain cells. Calcium is critical to regulating the release of neurotransmitters, the chemicals that brain cells use to communicate.

The functional gates, called calcium channels, are composed of four protein subunits, and the newly discovered stargazer mouse gene encodes the fourth or gamma subunit of the channel. The stargazer mutation results in the nearly complete absence of the gamma subunit protein, named stargazin, thereby altering the ability of the assembled calcium channel to properly control the flow of calcium into a nerve cell, explains Campbell.

"If you think of a calcium channel as a gate controlling calcium flow into the cell, then in normal mice, about 75 percent of the gates would be able to open," Campbell said. "But in the mutant mice lacking stargazin, all of the gates would be able to open. We believe that the increased flow of calcium that results causes an abnormal firing of brain cells." Stargazer mice get their name from the way in which the animals toss their heads during the 100 or more seizures, each lasting about 6 seconds, they experience each hour.

Epilepsy is a neurological disorder that occurs in about 20 forms and affects approximately one percent of the U.S. population. Absence, or petit mal, epilepsy occur
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
27-Jul-1998


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