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Stargazer gene provides new clues to calcium channel defects in absence
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
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,
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.