"This paper is a good example of how gene discovery is useful for giving clues about therapeutic targets and strategies, which is the most important goal of human gene discovery research in my view," says Katrina Gwinn-Hardy, M.D., the NINDS program director for Dr. Pulst's grant.
Through cell culture experiments, the researchers learned that the KCNC3 mutations in the Filipino and French families affect the potassium channel very differently. The mutation found in the Filipino family completely prevented the potassium channel from functioning. The mutation from the French family caused potassium channels to open earlier than normal and close too late. This reduced the rate at which the neurons could fire.
Researchers have long known that potassium channels are important for neuronal function. Mutations in other potassium channel genes have been linked to problems such as epilepsy, cardiac arrhythmias, and periodic muscle paralysis. One type of potassium channel defect has also been found in a disorder called episodic ataxia type 1 that causes brief episodes of ataxia without neurodegeneration. However, potassium channel mutations have never before been linked to neurodegenerative disease or mental retardation. The findings were surprising because mice lacking the KCNC3 gene have only mild behavioral changes, Dr. Pulst says.
It is not yet clear exactly how the potassium channel mutations cause neurodegeneration. One theory is that the mutations might increase the amount of calcium that can enter cells, causing them to die because o
'"/>
Contact: Natalie Frazin or Paul Girolami
301-496-5924
NIH/National Institute of Neurological Disorders and Stroke
26-Feb-2006