In addition to the progressive muscle weakness and degeneration common to all forms of muscular dystrophy, patients with the most common form of muscular dystrophy affecting adults, myotonic dystrophy type 1 (DM1), also experience an inability to voluntarily relax the muscles (a problem known as myotonia). DM1 originates from complex genetic mutations that result in abnormalities of the muscle proteins, including the muscle-specific chloride channel ClC-1.
Working under the theory that abnormal inclusion of a region of the ClC-1 gene known as exon 7a in the ClC-1 mRNA (the intermediate between gene and protein) may play a role in the development of DM1, Charles Thornton and his colleagues at the University of Rochester, Rochester, discovered a powerful method of correcting this aberrant exon 7a inclusion and reversing myotonia in mouse models of DM1. A nucleic acid compound known as a morpholino antisense oligonucleotide was generated that would allow the muscle cells to “skip” over the erroneously included exon7a. When this compound was injected into mice with DM1-like disease, exclusion of the extra genetic segment in the ClC-1 mRNA restored the function of ClC-1 protein and eliminated myotonia in the mice. The authors therefore suggested that it might be possible to use this approach to treat myotonia in individuals with DM1.
TITLE: Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy
AUTHOR CONTACT:
Charles A. Thornton
University of Rochester, Rochester, New York, USA.
Phone: (585) 275-2542; Fax: (585) 273-1255; E-mail: charles_thornton@urmc.rochester.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33355
Journal
Journal of Clinical Investigation