Breakthrough in Understanding Disease-Causing DNA Instability

Richard Sinden, Ph.D.
Texas A&M University
R01ES05508

Background: Genes in normal individuals contain short lengths of trinucleotide repeats in which a combination of nucleotides, the building blocks of DNA, are repeated a number of times, usually less than 30. Research has identified 18 human genetic diseases associated with expansion of the number of these repeats, sometimes numbering in the thousands. Fragile X syndrome, myotonic dystrophy, and Huntington's disease are few of these devastating diseases, which become increasingly severe and have earlier onsets in successive generations, a process known as anticipation. Scientists have theorized that if the cause of the repeat expansion can be discovered, there is hope in preventing them from occurring.

Advance: Researchers at Texas A&M University recently discovered that a repeat associated with spinocerebellar ataxia type 10 (SCA 10) is unlike any repeat identified to date. The repeat is made up of 10 nucleotides in the sequence (ATTCT)_n·(TAAGA) _n. Experiments demonstrated that the repeat unpairs and acts as a false site of DNA replication.

Implication: While it remains to be seen if repeats associated with other expansion-related diseases support incorrect DNA replication initiation, this finding gives researchers a new target on which to focus. It also sheds light on the mechanism of repeat expansion and may lead to further discoveries on how to prevent and repair these genetic defects.

Citation: Potaman VN, Bissler JJ, Hashem VI, Oussatcheva EA, Lu L, Shlyakhtenko LS, Lyubchenko YL, Matsuura T, Ashizawa T, Leffak M, Benham CJ, Sinden RR. Unpaired Structures in SCA10 (ATTCT)(n)·(AGAAT)(n) Repeats. J Mol Biol. 2003 Feb 28;326(4):1095-111.