Expanded CUG Repeats Trigger Aberrant Splicing of ClC-1 Chloride Channel Pre-mRNA and Hyperexcitability of Skeletal Muscle in Myotonic Dystrophy

• Published in: Molecular cell Vol. 10; no. 1; pp. 35 - 44
• Main Authors: Mankodi, Ami, Takahashi, Masanori P., Jiang, Hong, Beck, Carol L., Bowers, William J., Moxley, Richard T., Cannon, Stephen C., Thornton, Charles A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2002
• Subjects: Alternative Splicing - genetics; Animals; Base Sequence; Chloride Channels - genetics; Chloride Channels - metabolism; Disease Models, Animal; Electrophysiology; Humans; Membrane Potentials; Mice; Mice, Transgenic; Molecular Sequence Data; Muscle Fibers, Skeletal - metabolism; Muscle Fibers, Skeletal - pathology; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Myotonic Dystrophy - genetics; Myotonic Dystrophy - pathology; Myotonic Dystrophy - physiopathology; RNA Precursors - genetics; RNA Precursors - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Trinucleotide Repeat Expansion - genetics
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/S1097-2765(02)00563-4

In myotonic dystrophy (dystrophia myotonica, DM), expression of RNAs that contain expanded CUG or CCUG repeats is associated with degeneration and repetitive action potentials (myotonia) in skeletal muscle. Using skeletal muscle from a transgenic mouse model of DM, we show that expression of expanded CUG repeats reduces the transmembrane chloride conductance to levels well below those expected to cause myotonia. The expanded CUG repeats trigger aberrant splicing of pre-mRNA for ClC-1, the main chloride channel in muscle, resulting in loss of ClC-1 protein from the surface membrane. We also have identified a similar defect in ClC-1 splicing and expression in two types of human DM. We propose that a transdominant effect of mutant RNA on RNA processing leads to chloride channelopathy and membrane hyperexcitability in DM.