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NEUROLOGY 2008;70:677-685
© 2008 American Academy of Neurology

Aberrantly spliced {alpha}-dystrobrevin alters {alpha}-syntrophin binding in myotonic dystrophy type 1

M. Nakamori, MD, PhD, T. Kimura, MD, PhD, T. Kubota, MD, T. Matsumura, MD, PhD, H. Sumi, MD, PhD, H. Fujimura, MD, PhD, M. P. Takahashi, MD, PhD and S. Sakoda, MD, PhD

From the Department of Neurology, Osaka University Graduate School of Medicine (M.N., T. Kimura, T. Kubota, H.S., M.P.T., S.S.); and Department of Neurology, Toneyama National Hospital (T.M., H.F.), Osaka, Japan. Dr. Kimura is currently with the Division of Neurology, Department of Internal Medicine, Hyogo College of Medicine, Japan.

Address correspondence and reprint requests to Dr. Masanori P. Takahashi, 2-2, D-4, Yamadaoka, Suita, Osaka, Japan 565-0871 mtakahas{at}neurol.med.osaka-u.ac.jp

Background: Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by a CTG repeat expansion in the DMPK gene. Aberrant messenger RNA (mRNA) splicing of several genes has been reported to explain some of the symptoms in DM1, but the cause of muscle wasting is still unknown. By contrast, many forms of muscular dystrophy are caused by abnormalities of the dystrophin–glycoprotein complex (DGC). {alpha}-Dystrobrevin is a key component of the DGC in striated muscle and plays important roles in maturation and signal transduction by interacting with {alpha}-syntrophin. The goal of this study was to investigate alternative splicing of {alpha}-dystrobrevin in DM1 and examine {alpha}-syntrophin binding of different {alpha}-dystrobrevin splice isoforms.

Methods: Splicing patterns of {alpha}-dystrobrevin in DM1 muscle were studied by reverse-transcriptase PCR. Expression of the variant splice isoform was examined by immunoblotting and immunohistochemistry. Alternatively spliced isoforms were expressed in cultured cells to investigate interaction with {alpha}-syntrophin. {alpha}-Syntrophin expression was examined by immunoblotting.

Results: {alpha}-Dystrobrevin mRNA including exons 11A and 12 was increased in both skeletal and cardiac muscle of DM1 patients. The aberrantly spliced {alpha}-dystrobrevin isoform was localized to the sarcolemma, and showed increased binding with {alpha}-syntrophin. Furthermore, levels of {alpha}-syntrophin associated with the DGC were increased in DM1 muscle.

Conclusion: Alternative splicing of {alpha}-dystrobrevin is dysregulated in myotonic dystrophy type 1 (DM1) muscle, resulting in changes in {alpha}-syntrophin binding. These results raise the possibility that effects on {alpha}-dystrobrevin splicing may influence signaling in DM1 muscle cells.

GLOSSARY: {alpha}-DB = {alpha}-dystrobrevin; {alpha}-syn = {alpha}-syntrophin; ALS = amyotrophic lateral sclerosis; β-DG = β-dystroglycan; CC = coiled-coil domain; cDM = congenital myotonic dystrophy type 1; cDNA = complementary DNA; Cont = control; DAPC = dystrophin-associated protein complex; DBS = dystrophin binding site; DGC = dystrophin–glycoprotein complex; DM1 = myotonic dystrophy type 1; EF = EF hand region; GAPDH = glyceraldehyde 3-phosphate dehydrogenase; IP = immunoprecipitation; LGMD = limb-girdle muscular dystrophy; MDRS = muscular disability rating scale; mRNA = messenger RNA; NA = not available; NMJ = neuromuscular junction; NT = not tested; P = postnatal day; PM = polymyositis; RT-PCR = reverse-transcriptase PCR; SBS = syntrophin binding site; SDS-PAGE = sodium dodecyl sulfate polyacrylamide gel electrophoresis; TBS = Tris-buffered saline; WCL = whole-cell lysate; vr = variable region; Y = unique tyrosine kinase substrate domain; ZZ = zinc-binding domain.

Supplemental data at www.neurology.org

Supported by a Research Grant (17A-10) from the Ministry of Health, Labor, and Welfare, Japan (S.S.), and Grants-in-Aid from the Japan Society for the Promotion of Science (M.P.T.).

Disclosure: The authors report no conflicts of interest.

Received June 21, 2007. Accepted in final form September 17, 2007.






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