July 28, 1998 BAR HARBOR, Maine -- Researchers at The Jackson Laboratory and colleagues have identified the gene for the epilepsy mutation in mice known as "stargazer" and report that the novel gene, Cacng2, produces a defect in a neuronal calcium channel that may play a key role in absence, or petit mal, epilepsy.
The research paper, "The mouse stargazer encodes a neuronal Ca2+-channel gamma subunit," is published in the August issue of the scientific journal Nature Genetics by a team led by Drs. Verity A. Letts and Wayne N. Frankel of The Jackson Laboratory, in collaboration with Dr. Kevin P. Campbell of the Howard Hughes Medical Institute at the University of Iowa College of Medicine.
"This confirms the role of calcium channels in mouse models for absence epilepsy," says Dr. Frankel. "Identification of the stargazer gene provides a new opportunity to better understand how these channels function in the mammalian brain and how they may be targeted in the treatment of neuroexcitability disorders, including epilepsy, in humans."
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 1 to 7 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, Dr. Frankel says.
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.
The Jackson Laboratory researchers had previously reported in the journal Genomics (1997) the fine-mapping of the single-gene, recessive stargazer mutation to mouse Chromosome 15, and have now characterized the gene -- Cacng2, or calcium channel gamma 2 subunit -- in which the mutation resides. The brain-specific protein that Cacng2 encodes has been named "stargazin."
Calcium channels are a diverse family of proteins which 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 and are called beta, alpha 2/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 may allow excessive amounts of calcium ions to flow into the nerve, which leads to abnormal firing of neurons.
Cacng2 is the most recent accomplishment in the ongoing research effort by the Jackson Laboratory group since 1992 to identify new gene defects in mouse models for epilepsy. Cacng2 is a regulatory subunit of the first absence epilepsy gene discovered, Cacna1a, which occurred in a Jackson Laboratory mouse called "tottering" as reported in the journal Cell (1996). That discovery was made jointly by Dr. Frankel with a research team from the NCI Frederick Cancer Research and Development Center in Maryland. Also reported in Cell (1997), the group previously found that the defective gene in the "slow-wave epilepsy" (swe) mouse was a well-known cell membrane ion transporter called Nhe1.
According to the Jackson Laboratory researchers, the stargazer finding is perhaps the most exciting because Cacng2 is a new gene, representing 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. "We have shown that this new gene is critical for normal central nervous system function," says Dr. Letts, "and it suggests an important role in seizure disorders."
The stargazer research at The Jackson Laboratory was supported by a grant to Dr. Letts from the National Institutes of Health and to Dr. Frankel from the Klingenstein Fellowship in the Neurosciences. Dr. Campbell is an investigator of the Howard Hughes Medical Institute.
### The Jackson Laboratory, founded in 1929, is a world leader in mammalian genetics research. With more than 850 employees, the nonprofit, independent facility has a three-fold mission: to conduct basic genetic and biomedical research, train present and future scientists, and provide genetic resources to researchers worldwide.
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