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Faulty DNA replication linked to neurological diseases

Lengthy sequences of DNA -- with their component triplet of nucleotides repeated hundreds, even thousands of times -- are known to be abnormal, causing rare but devastating neurological diseases. But how does the DNA get this way? How does it go haywire, multiplying out of control?

In the current issue of Molecular and Cellular Biology, Sergei Mirkin, professor of biochemistry and molecular genetics at the University of Illinois at Chicago College of Medicine, explains the mechanism, providing an important clue to the origin of these diseases.

Mirkin and Maria Krasilnikova, a research assistant professor in his lab, studied the sequence of a simple repeat of three nucleotides responsible for Friedreich's ataxia, the most commonly inherited form of ataxias, which causes progressive damage to the nervous system, resulting in symptoms ranging from muscle weakness and speech problems to heart disease.

The DNA triplet that repeats in Friedreich's ataxia is a guanine and two adenines (GAA) on one DNA strand and the complementary two thymines and a cytosine (TTC) on the opposite strand.

Earlier research had shown that up to 40 repeats of this nucleotide triplet do not cause any symptoms. The DNA is inherited as is, an odd but harmless pattern passed down from one generation to the next.

The problems begin when the repeats exceed 40.

"For Friedreich's ataxia and other neurological diseases, when the number of repeats exceeds 40, the sequence becomes unstable. That means that as the sequence is passed from one generation to the next, it gets longer. The longer it gets, the more likely it will get still longer. And the longer it gets, the worse the disease," Mirkin said. "Basically, even if you are more or less okay, there is a probability that your kids will be sick and a still higher probability that your grandkids will be even sicker."

To study how and why the inherited sequence expands so rapidly, the scientists wat
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Contact: Sharon Butler
sbutler@uic.edu
312-355-2522
University of Illinois at Chicago
4-Mar-2004


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