Triplet Repeats in the Myotonic Dystrophy Gene

Robert D. Wells
Texas A&M University
R01ES11347

Background: A recent report by Richard Sinden of Texas A&M University (J Mol Biol. 326(4):1095-11) described an unusual trinucleotide repeat sequence in the gene for spinocerebellar ataxia type 10. 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. Eighteen human genetic diseases have been associated with expansion of the number of these repeats, sometimes numbering in the thousands. These diseases often become increasingly severe and have earlier onsets in successive generations.

A new study, from a different research team at Texas A&M, sheds light on repeat expansions in the gene for Myotonic Dystrophy (DM). DM is the most common inherited neuromuscular disease in humans affecting one in 8,000 people worldwide.

Advance: This paper describes a model system in which repeats of the trinucleotide sequence CTG from the DM gene are deposited into an intron in one copy of a tandemly duplicated pair of APRT genes. Selecting for homologous recombination between the duplicated copies of the gene enables the examination of changes to the inserted CTG repeats in cells located nearby a recombination event. Long CTG repeats experienced large contractions and generated a high frequency of rearrangements. Replicating cells displayed a high frequency of expansions and contractions that usually involve a small number of triplets. The results demonstrate that homologous recombination destabilizes long CTG repeats in this cell system.

Implication: The roles of contraction and rearrangements of trinucleotide repeat sequences, along with other aspects of DNA metabolism, in the development of triplet repeat diseases is unclear. This model offers insights on the mechanism of repeat expansion and may lead to further discoveries on how to prevent or repair these genetic defects. Scientists have theorized that if the cause of the repeat expansion can be discovered, there is hope in preventing them from occurring.

Citation: Meservy JL, Sargent RG, Iyer RR, Chan F, McKenzie GJ, Wells RD, Wilson JH. Long CTG tracts from the myotonic dystrophy gene induce deletions and rearrangements during recombination at the APRT locus in CHO cells. Mol Cell Biol. 2003 May;23(9):3152-62.