Ataxia

Edited by: Paul Smaglik and Eugene Russo O. Zhuchenko, J. Bailey, P. Bonnen, T. Ashizawa, D.W. Stockton, C. Amos, W.B. Dobyns, S.H. Subramony, H.Y. Zoghbi, C.C. Lee, "Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha(1A)-voltage-dependent calcium channel," Nature Genetics, 14:62-9, January 1997. (Cited in more than 210 papers since publication) Comments by Cheng Chi Lee, assistant professor, molecular and human genetics, Baylor College of Medicine, and S.H. Subramony, professor and vice chairman, neurology, University of Mississippi School of Medicine Sometimes, to go forward, you have to work backward. Cheng Chi Lee and colleagues did just that in identifying the SCA6 gene. Rather than adapt the traditional method of positional cloning--identifying a gene based on a family, pinning it to a general map, identifying a chromosome, then working toward a specific location--they started with what they knew. "They decided to look at genes that were expressed in the brain and that had CAG repeats," says S.H. Subramony, who supplied patients, but didn't assist directly in the gene hunt. CAG repeats had characterized all other known forms of inherited progressive ataxia at the time. Cheng Chi Lee Lee recalls that two assumptions guided his gene hunt: that human genes are 99 percent genetically identical to one another and that people with similar disorders likely have common genes involved. Those assumptions opened the search to a population with common clinical traits. "What we found was, lo and behold, in that subpopulation, there were eight individuals who had a CAG repeat that was much bigger than normal, that was not seen in the other diseases," Lee explains. The researchers then genotyped the eight patients against other disease models. "Then we went back to these eight individuals and asked if they had family members that had the same disorder. This is where Dr. Subramony's collection came in, because, in fact, the index cases came from him." The final proof came from that collection. "The affected had the expanded repeat and the nonaffected did not have the repeat. And that is the proof." Fortunately, Lee had made no assumptions about the size of the CAG repeat. Conventional wisdom held that a gene must contain 35 or more CAG repeats to cause a disorder. That had been the case in the other known SCA genes, as well as in Huntington's disease and Kennedy's disorder. In one patient, a 21-CAG repeat proved large enough to cause the disorder. Lee double-checked through genotyping that this 21 repeat was not present in the normal population. Subramony notes that the group was also fortunate that the CAG repeats it had been searching for appeared, since the assumption may not hold true that the repeat is involved in all forms of inherited ataxias. "As of last year, all of the progressive, dominant ataxias had CAG repeat expansions as the underlying mechanism," Subramony notes. "Very recently, a disorder called SCA8 has been described that does not involve CAG repeats." Also, episodic ataxias do not involve CAG repeats. Indeed, since identifying the gene, other researchers have identified mutations to the SCA6 gene not involved in CAG repeats that cause different disorders. Missense mutations on the same gene lead to familiar hemiplegic migraine. Splice mutations there cause episodic ataxias. Subramony and Lee agree that those drastic allelic variations have attracted attention to the paper--especially since all three variations involve damage to different parts of the same protein: alpha 1 subunit A. That protein is an ion channel protein, responsible for passing calcium through a cell's membrane. "I think the idea that abnormalities in channel proteins cause disease is an interesting one," Subramony says. "The understanding of mutations in channel proteins has given us the idea that these diseases that [come] in short episodes, may all be potentially related to channel protein defects." Both researchers have identified crucial research questions to explore. Lee is exploring the electrophysiology of the calcium channel activity in relation to CAG repeat length and attempting to construct a valid mouse model; current attempts to do so have led to mice with epilepsy. Subramony is interested in the diversity of the mutations and is curious about how damaging different parts of the same channel protein can cause different diseases. "The research activity is finding more gene mutations, more defects in channel proteins, and then trying to figure out why these mutations cause disease." In addition, both researchers expect more genes associated with different forms of ataxia to be identified in the near future.

Ataxia

The Scientist Staff

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