Human Molecular Genetics Advance Access published online on June 22, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi223
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1 Division of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, PO Box 334, Canberra, ACT 2601, Australia; Department of Neurology, Osaka University Graduate School of Medicine, D-4, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
* To whom correspondence should be addressed. Myotonic dystrophy type 1 (DM1) is a debilitating multisystemic disorder caused by a CTG repeat expansion in the DMPK gene. Aberrant splicing of several genes has been reported to contribute to some symptoms of DM1, but the cause of muscle weakness in DM1 and elevated Ca2+ concentrations in cultured DM muscle cells is unknown. Here we investigated the alternative splicing of mRNAs of two major proteins of the sarcoplasmic reticulum, the ryanodine receptor 1 (RyR1) and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) 1 or 2. The fetal variants, ASI(-) of RyR1 which lacks residue 3481-3485, and SERCA1b which differs at the carboxyl-terminus, were significantly increased in skeletal muscles from DM1 patients and the transgenic mouse model of DM1 (HSALR). In addition, a novel variant of SERCA2 was significantly decreased in DM1 patients. The total amount of mRNA for RyR1, SERCA1 and SERCA2 in DM1 and the expression levels of their proteins in HSALR mice were not significantly different. However, heterologous expression of ASI(-) in cultured cells showed decreased affinity for [3H]ryanodine but similar Ca2+ dependency, and decreased channel activity in single channel recording, compared with wild type (ASI(+)) RyR1. In support of this, RyR1-knockout myotubes expressing ASI(-) exhibited a decreased incidence of Ca2+ oscillations during caffeine exposure compared to that observed for myotubes expressing wild type RyR1. We suggest that aberrant splicing of RyR1 and SERCA1 mRNAs might contribute to impaired Ca2+ homeostasis in DM1 muscle.
Received May 2, 2005
Revised June 16, 2005
Accepted June 16, 2005
Article
Altered mRNA Splicing of the Skeletal Muscle Ryanodine Receptor and Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase in Myotonic Dystrophy Type 1
2 Department of Neurology, Osaka University Graduate School of Medicine, D-4, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
3 Department of Pharmacology and Physiology, University of Rochester Medical Center, PO Box 711, 601 Elmwood Avenue, Rochester, NY 14642, USA
4 Division of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, PO Box 334, Canberra, ACT 2601, Australia
Masanori P. Takahashi, E-mail: mtakahas{at}neurol.med.osaka-u.ac.jp
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