Huntington's disease–like 2 is associated with CUG repeat-containing RNA foci
Version of Record online: 23 MAR 2007
Copyright © 2007 American Neurological Association
Annals of Neurology
Volume 61, Issue 3, pages 272–282, March 2007
How to Cite
Rudnicki, D. D., Holmes, S. E., Lin, M. W., Thornton, C. A., Ross, C. A. and Margolis, R. L. (2007), Huntington's disease–like 2 is associated with CUG repeat-containing RNA foci. Ann Neurol., 61: 272–282. doi: 10.1002/ana.21081
- Issue online: 23 MAR 2007
- Version of Record online: 23 MAR 2007
- Manuscript Accepted: 15 DEC 2006
- Manuscript Revised: 12 DEC 2006
- Manuscript Received: 14 AUG 2006
- Hereditary Disease Foundation (Lieberman Award; John J. Wasmuth fellowship)
- NIH (NINDS). Grant Numbers: NS16375, NS38054
Huntington's disease–like 2 (HDL2) is caused by a CAG/CTG expansion mutation on chromosome 16q24.3. The repeat falls, in the CTG orientation, within a variably spliced exon of junctophilin-3 (JPH3). The existence of a JPH3 splice variant with the CTG repeat in 3′ untranslated region suggested that transcripts containing an expanded CUG repeat could play a role in the pathogenesis of HDL2, similar to the proposed pathogenic role of expanded CUG repeats in myotonic dystrophy type 1 (DM1). The goal of this study, therefore, was to test the plausibility of an RNA gain-of-function component in the pathogenesis of HDL2.
The presence and composition of RNA foci in frontal cortex from HDL2, Huntington's disease, DM1, and control brains were investigated by in situ hybridization and immunohistochemistry. An untranslatable JPH3 transcript containing either a normal or an expanded CUG repeat was engineered and expressed in human embryonic kidney 293 and HT22 cells to further test the toxic RNA hypothesis. The formation of RNA foci and the extent of cell death were quantified.
RNA foci resembling DM1 foci were detected in neurons in HDL2 cortex and other brain regions. Similar to DM1, the foci colocalize with muscleblind-like protein 1, and nuclear muscleblind-like protein 1 in HDL2 cortical neurons is decreased relative to controls. In cell experiments, expression of a JPH3 transcript with an expanded CUG repeat resulted in the formation of RNA foci that colocalized with muscleblind-like protein 1 and in cell toxicity.
These results imply that RNA toxicity may contribute to the pathogenesis of HDL2. Ann Neurol 2007;61:272–282