Journal
MOLECULAR CELL
Volume 10, Issue 1, Pages 35-44Publisher
CELL PRESS
DOI: 10.1016/S1097-2765(02)00563-4
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Funding
- NCRR NIH HHS [RR00044] Funding Source: Medline
- NIAMS NIH HHS [AR44069, AR46806, AR42703] Funding Source: Medline
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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 CIC-1, the main chloride channel in muscle, resulting in loss of CIC-1 protein from the surface membrane. We also have identified a similar defect in CIC-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.
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