Suppression of Absence Epilepsy Seizures Dependent on Complex Balance of Proteins According to Jackson Laboratory Research Findings

Date: January 25, 2005

Bar Harbor, Maine - In her studies of absence epilepsy - a generalized form of epilepsy most commonly diagnosed in children and characterized by brief losses of consciousness - Research Scientist Dr. Verity Letts and colleagues at The Jackson Laboratory have discovered that a complex balance of closely associated proteins expressed in the brain work together to suppress seizures. Dr. Letts' findings are published in the January 25 issue of the Proceedings of the National Academy of Sciences.

Stargazer, a mouse model of absence epilepsy seizures in humans discovered at Jackson, makes virtually no CACNG2 protein due to a disruption of the Cacng2 gene responsible for its production. Stargazer's distinctive phenotype includes an ataxic gait, frequent absence seizure episodes, and head elevation.

A homozygous Cacng4-targeted mutant mouse was engineered to assess the function of the CACNG4 protein. The mutant appears normal, exhibiting no ataxia or absence seizures; the researchers suggest that closely associated proteins may compensate for the lack of CACNG4. When bred with the two stargazer allelic mutants, waggler and stargazer 3J (a mouse model that does not exhibit seizures), absence seizures occurred in the resulting double mutant offspring.

"We have found that the Cacng4-targeted homozygous mutant is overtly normal. However, by combining this mutation with mutations in the Cacng2 gene, there is an overall increase in absence seizures," explained Dr. Letts. "These results indicate that the CACNG2 protein compensates for the loss of CACNG4 protein. However, if both proteins are reduced in the same mouse, the prevalence of seizures is increased, revealing that both CACNG2 and CACNG4 are involved in suppressing absence seizure activity."

Epilepsy is the most common neurological condition in the human population, affecting about 2.5 million Americans in the past five years.

With more than 1,300 employees and an FY05 operating budget of $130.1 million, the nonprofit, 75-year-old Jackson Laboratory is one of Maine's largest employers. Its research staff of more than 465 investigates the genetic basis of cancers, heart disease, osteoporosis, Alzheimer's disease, glaucoma, diabetes, and many other human diseases and disorders. The Laboratory is also home of the Mouse Genome Database and many other publicly available information resources, and is also an international hub for scientific courses, conferences, training and education-including programs for Maine high school, college, and graduate students.

Letts VA, Mahaffey CL, Beyer B, Frankel WN. 2005. A targeted mutation in Cacng4 exacerbates spike-wave seizures in stargazer (Cacng2) mice. PNAS.

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Joyce Peterson, 207-288-6058, joyce@jax.org

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