Suppression of Absence Epilepsy Seizures Dependent on Complex Balance of Proteins
JAX® NOTES Issue 497, Spring 2005
Epilepsy is one of the most common disorders of the nervous system, affecting 2.5 million Americans of all ages, races, and ethnic backgrounds. Every year, 181,000 Americans develop epilepsy. Although epileptic seizures vary outwardly, they are all brought about by brief electrical disturbances in the brain. One form of epilepsy, absence or petit mal epilepsy, is most commonly diagnosed in children and is characterized by brief losses of consciousness. Jackson Laboratory Research Scientist Dr. Verity Letts and her colleagues study absence epilepsy and have discovered that seizures can be suppressed by a complex balance of closely interacting proteins expressed in the brain.
As models, Dr. Letts used JAX® Mice strains B6C3Fe a/a-Cacng2stg/J (Stock Number 001756), commonly known as "stargazer," B6.MRL-Cacng2stg-wag/J (Stock Number 001883), commonly known as "waggler," and stargazer 3 Jackson (a JAX® Mice strain not publicly available). Stargazer was so named because of its abnormal choreiform-like head movements, ataxic (clumsy) gait, and frequent episodes of absence seizures; waggler's phenotype is less severe than stagazer's, exhibiting seizures only occasionally; stargazer 3 Jackson does not exhibit seizures. The abnormal phenotype of each of these three models is due to a mutation in the voltage-dependent calcium channel (VDCC) gamma subunit gene, Cacng2, which plays a key role in maintaining normal electrical activity in the brain. Stagazer makes virtually no CACNG2, the protein encoded by Cacng2. To assess the role of closely related protein CACNG4 (encoded by Cacng4) Letts and her colleagues engineered a homozygous Cacng4-targeted mutant mouse, a Cacng4 "knockout." The knockout, which had a normally functioning Cacng2 gene, appeared normal, exhibiting neither ataxia nor absence seizures. Suspecting that closely associated proteins like CACNG2 were compensating for the lack of CACNG4, Letts and colleagues bred the Cacng2 knockout to waggler and stargazer 3 Jackson. Not only did the offspring have absence seizures, but they had more of them.
Dr. Letts' results indicate that the CACNG2 protein compensates for the loss of CACNG4 protein. In the absence of both proteins, the prevalence of seizures increases, revealing that both are involved in maintaining normal electrical activity in the brain.
References:
(Authors in bold are Jackson Laboratory scientists)
Letts VA, Mahaffey CL, Beyer B, Frankel WN. 2005. A targeted mutation in Cacng4 exacerbates spike-wave seizures in stargazer (Cacng2) mice. Proc Natl Acad Sci U S A 102:2123-8.
This story has been adapted from a news release issued by The Jackson Laboratory.
