Identification of two nuclear proteins which bind to RNA CUG repeats: significance for myotonic dystrophy.

Myotonic dystrophy is caused by a trinucleotide repeat expansion (CTG)n, located in the 3' untranslated region of the DM-protein kinase gene. The cellular effects of the CTG expansion and how they lead to the diverse, multi-system clinical phenotype of DM are unknown. Studies on the expression of the DM gene in affected tissue have not yielded consistent results, leading to the suggestion that alterations of DM-PK may not be the sole molecular basis for DM. We explored the hypothesis that the expanded repeat in mutant DM RNA (CUG)n binds and titrates out nuclear RNA binding proteins. Alterations in the normal function of these proteins could result in the disruption of important cellular processes. We report here the identification and magnetic bead affinity purification of two nuclear proteins, 35 and 25 kD in size, which bind to RNA (CUG)n repeats and to a varying extent with other pyrimidine rich sequences. Sequence analysis of the 35 kD protein shows that it is a novel protein. Both these proteins are widely expressed, including human brain and skeletal muscle. We speculate that these proteins may play a role in DM pre-mRNA processing or nuclear cytoplasmic trafficking of RNA. Studies into the function of these proteins should yield important insights into the complex pathogenesis of myotonic dystrophy.