Further genetic analyses of the particular mutation also showed why it occurred in the same place in all instances of the disease. That analysis revealed that the particular site of the mutation was a hotspot in the genome that was more prone to spontaneous mutation, said Keating.

"With these findings, we had a good handle on why this particular mutation would cause an arrhythmia and also how we could reduce the risk of arrhythmia in these children by blocking that channel," said Keating. The investigators hope that calcium-channel-blocking medications may reduce arrhythmia and improve cognitive function in this disorder.

"While there are developmental abnormalities that we can't treat, it is very gratifying for us and for the families of these children that we may be able to deal with some of their physiological abnormalities," said Keating.

According to Keating, discovery of the genetic basis of Timothy syndrome has implications for understanding the function and importance of calcium channels in general. "Our findings showed that the mutated region is required for inactivation of the channel, which was not previously appreciated," he said. "More broadly, this finding really highlights in a way that I haven't seen before the fundamental importance of calcium metabolism in development and physiology in humans."

While Keating emphasized that autism remains a deeply mysterious and complex disorder, "it certainly is a reasonable hypothesis that abnormal calcium signaling could contribute to the disorder in some cases," he said.

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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
30-Sep-2004