Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy.
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.
Mankodi
Ami
A
Department of Neurology, School of Medicine and Dentistry, University of Rochester, Box 673, 601 Elmwood Avenue, New York 14642, USA.
Takahashi
Masanori P
MP
Jiang
Hong
H
Beck
Carol L
CL
Bowers
William J
WJ
Moxley
Richard T
RT
Cannon
Stephen C
SC
Thornton
Charles A
CA
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D004594:Electrophysiology; D006801:Humans; D008564:Membrane Potentials; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology*; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
C086321:CLC-1 channel; D018118:Chloride Channels; D012322:RNA Precursors; D012333:RNA, Messenger