Surprising discovery in SCA8 research.(Spinocerebellar ataxia type 8)(Clinical report)

Thank you for the opportunity to talk about our work on SCA8. SCA1, 2, 3 and a number of the other ataxias are caused by polyglutamine expansions that for long time have been known to be part protein coding regions in their respective genes. SCA8 has parallels to both the polyglutamine ataxias and to ataxias in which the repeat appears to be located in a region of the gene that does not encode a protein including SCA10 and SCA12.

So why find and study new ataxia genes and why study unusual genes like SCAB? This question makes me think of a book by Eric Carle that I read to my children a long time ago that made an impression on me. This is a story about an elephant and seven blind mice. There was a sick animal in the rain forest and the blind mice needed to go and figure out what the animal could be. One of them went out and ran into the elephant's foot and decided that it was a pillar. Another went and found the tail and came back and said that it was a rope. Another mouse found the ear and said, "It wasn't a rope, it was a butterfly." Another found the trunk and said that it wasn't a butterfly, that it was a snake.

I think that when we find new genes, we are in a sense, finding a different piece of the puzzle or a different part of the story. Each gene we find is similar to what the blind mice found because it is inevitably only part of the story. But as scientists when we compare these stories we get a better picture of the overall view and we hope that we can put together a picture of the elephant. And for ataxia, we hope we can put together a picture of what causes neurons in the brain to die.

I am going to talk about the Murphy Mouse that we made and about our surprising discovery during the past year that the SCA8 mutation is expressed by two different genes that run in opposite directions. And then I am going to tell you about our evidence for RNA gain of function effects of SCA8.

So we isolated the SCA8 expansion from a single individual. We isolated the gene and this expansion mutation directly from her DNA. Then we worked up a large family that is unrelated to her …