By David N. Leff
Even the most attentive new parents may overlook the first time or two that their small child suddenly stops what he or she is doing and stares vacantly into space.
After that brief interval of "losing it" — which lasts typically six seconds or so — the small person resumes whatever activity he or she was engaged in before the event, as if nothing had happened. Should this odd behavior repeat itself every minute or two, a pediatric neurologist is likely to diagnose mild epileptic seizures known to the profession as "petit mal" (French for "little illness") or by the more descriptive French term, "absence."
"Generally, affected children tend to outgrow absence as they become adults," observed molecular biologist and geneticist Verity Letts, at the Jackson Laboratory, in Bar Harbor, Maine. "But that's not invariably the situation," she continued. "Sometimes the absence epilepsy develops into the more serious convulsive seizures of gran mal [big illness]."
Letts is a research scientist in the laboratory of Wayne Frankel at Jackson Laboratory, which focuses on mouse models of human epilepsy.
She is first author and Frankel, senior author, of a paper in the August 1998 Nature Genetics titled: "The mouse stargazer gene encodes a neuronal Ca2+-channel g subunit."
Jackson is a premier source of laboratory rodents, purpose-bred to specific research requirements.
"Some time in the 1980s," Letts told BioWorld Today, "the stargazer mouse was discovered here. It was probably picked up in the production facility, where they breed mice for selling. They noticed that it had a strange head-cocking activity and an ataxic — unsteady — gait.
"So they brought the animal up to the research labs, right next door," she continued, "which studied it to determine whether it had a genetic inherited disorder. They found a recessive mutation. So its absence epilepsy is genetically inherited and maps to mouse chromosome 15. Then they determined that in addition to the head-cocking and unsteady gait — for which they named it 'stargazer' — it had spike-wave discharge disorders, characteristic of those spontaneous petit mal seizures.
"If you didn't have the electroencephalogram brain-wave measurements," Letts pointed out, "you wouldn't know that the mouse was having absence seizures on average every six seconds, over 100 times an hour."
She made the point, "The human homologous region to mouse chromosome 15 is the long arm of human chromosome 22. And so far, no human absence epilepsy could be mapped to this region, so there's no human counterpart that we know of."
Stable Of Lapsed-Consciousness Rodents
Stargazer joined a roster of previously discovered mutant animals — namely, ducky, lethargic, mocha, tottering — that mimicked the hallmarks of human absence epilepsy. Besides these visible tip-offs, all shared aberrant electroencephalograms, spike-wave brain arrest, characteristic of petit mal epilepsy.
As reported in Nature Genetics, the novel gene Frankel's group discovered, Cacng2, encodes a 36-kiloDalton protein, which was dubbed "stargazin."
"What we did," Letts recounted, "was find mutations residing in that gene, which encodes what we believe to be a defective neuronal calcium channel gamma subunit." Cacng2 stands for calcium channel neuron gamma.
"Calcium channels," she explained, "play very important roles in the brain. Each channel is composed of four subunits. The major structural subunit is called alpha 1. It's large and spans the brain cell's membrane, so it essentially forms the ion pore through which calcium ions flow. The other three — beta, alpha2/delta and gamma — are regulatory subunits. Up to now," she pointed out, "nobody knew there was a gamma subunit in the brain. So this is the first time we have shown that there is indeed a specific brain gamma subunit, and the stargazin gene encodes it.
"The primary reason," she added, "why the stargazer mouse has absence epilepsy appears to be the fact that it has a mutation in this gamma subunit."
To arrive at this determination, the co-authors "narrowed down the mutation, and then discovered that it was an insertion in an intron in a gene. So we picked out the entire novel gene. At the DNA level it appears to have no homology to any other isolated gene."
But what the team discovered was that the gene product's 323-amino-acid structure had 25 percent identity with a skeletal-muscle gamma subunit. "That's part of the reason," Letts said, "how we determined that it was indeed the brain calcium channel gamma subunit.
"Up to now," she related, "the in vitro studies that have been done with calcium channels, especially neuronal ones, have not included this gamma subunit. So now we can include it and essentially complete all the major subunits that are usually associated with calcium channels.
"We can look to see if therapeutics and drug applications can now be completed on the entire native channel, as it were.
"Calcium channels," Letts went on, "are enriched in neuronal cells, especially synapses. What they do is allow calcium to flow into the cell and there mediate a number of different pathways. These include release of neurotransmitters, second-messenger activations and protein signaling.
"We believe the gamma subunit has mostly to do with inactivating the channel, turning it off to prevent calcium flow from continuing abnormally. So in stargazer we suspect that because it has a defect in this particular gene, it permits excessive calcium flux into the cell. And that presumably triggers a number of inappropriate mechanisms that eventually lead to epilepsy. But we don't know the intermediate steps at the moment."
In Febrile Epilepsy, Sodium Channels Go Awry
A companion paper in the same August issue of Nature Genetics bears the title: "Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel ß1 subunit gene SCN1B." Its senior author is molecular geneticist John Mulley, at the Women's and Children's Hospital, in North Adelaide, Australia.
Up to 3 percent of all children under six years of age go into convulsions when they have a high fever. This syndrome, said Mulley, "is by far the most common seizure disorder." It has an inherited predisposition and 2 percent of affected patients go on to develop full-blown epilepsy.
He and his co-authors studied a six-generation extended family in Tasmania, 42 of whose members had a history of seizures. Linkage analysis disclosed a mutant gene, which encoded a defective sodium channel protein, reminiscent of the Jackson Laboratory report's calcium channel subunit. *