Jeffrey L. Noebels, M.D., Ph.D. (left), and Ed Glasscock, Ph.D.
Two wrongs can make a right – at least in the genetics of the brain, said a Baylor College of Medicine researcher in a recent report in the journal Nature Neuroscience.
Specifically, the two wrongs are genetic changes or mutations that alone could each cause epilepsy, said Jeffrey L. Noebels, M.D., Ph.D., professor of neurology, neuroscience and molecular and human genetics at BCM. However, his research shows that inheriting the two genetic mutations might actually be "seizure-protective."
"We believe these findings have great significance to clinicians as we move toward relying on genes to predict neurological disease," said Noebels.
New treatment possible
In addition, the finding might point the way to new ways of treating epilepsy using gene-directed therapy.
"If you have a potassium channel defect, then a drug blocking certain calcium channels might also benefit you," said Noebels.
Noebels and his colleagues, who included first author Ed Glasscock, Ph.D., a postdoctoral researcher at BCM, tested this hypothesis by breeding mice with two defective genes that govern ion channels, tiny pores in cells that allow molecules such as potassium and calcium to flow in and out.
The genes were known to cause epilepsy when inherited singly within families. They have also been found in a large-scale screen of people with non-familial seizure disorders being performed in collaboration with the Baylor Human Genome Sequencing Center.
Affects of mutated genes separate vs. together
One is a mutation in the Kcna1 gene involved in the channel that allows potassium to flow in and out of the cell. It causes severe seizures affecting the brain's temporal lobe, an area of the brain involved in processing sight, sound, speech and forming memories. It can also cause sudden death in young mice.
The other mutation is in a calcium channel gene (Cacna1a) that causes a specific type of seizure associated with absence epilepsy. When people suffer these seizures, they may appear to be staring into space and do not exhibit the jerking or movements generally associated with epilepsy.
When both types of mutation occurred in the same young mouse, that animal had dramatically reduced seizures and did not suffer the sudden death associated with the potassium channel problem.
Gene profile may prove essential
Noebels, who is also director of the Developmental Neurogenetics Laboratory funded by the National Institutes of Health and Blue Bird Circle Foundation, said, "Rather than screening for 'bad' genes one at a time, it may be essential to create a complete profile of many or even all genes in order to accurately assess the true genetic risk of any single defect in many common disorders such as epilepsy. Fortunately, this amount of background information will soon become routinely obtainable in individual patients thanks to rapid technological progress in the field of neurogenomics."
Many different genes can lead to seizure disorders. In some cases, they encode ion channels that adjust the way neurons fire. Previous work indicated that combinations of such genes could make epilepsy worse. However, certain combinations may actually prevent the abnormal patterns of epilepsy, acting as "circuit breakers," said Noebels.
Others who took part in this study include Jing Qian and Jong W. Yoo, both of BCM. Funding for this work came from the National Institute of Neurological Disorders and Stroke.
The article can be found at http://www.nature.com/neuro/journal/vaop/ncurrent/pdf/nn1999.pdf.
Original source: www.bcm.edu/archives/fromthelab/vol06/is10/1207-3.html