Human Molecular Genetics Advance Access published online on March 10, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl045
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1 Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan
* To whom correspondence should be addressed. Recent studies have revealed an association between post-translational modification of
Received October 15, 2005
Revised February 28, 2006
Accepted March 28, 2006
Article
Aberrant neuromuscular junctions and delayed terminal muscle fiber maturation in
Mariko Taniguchi 1,
Hiroki Kurahashi 2,
Satoru Noguchi 3,
Takayasu Fukudome 4,
Takeshi Okinaga 5,
Toshifumi Tsukahara 6,
Youichi Tajima 7,
Keiichi Ozono 5,
Ichizo Nishino 3,
Ikuya Nonaka 3,
and
Tatsushi Toda 1 *
-dystroglycanopathies
2 Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan
3 National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan
4 Department of Neurology, Kawatana National Hospital, Kawatanamachi, Nagasaki 859-3615, Japan
5 Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871 Japan
6 Nano Materials and Technology Center, Advanced Institute of Science and Technology, Tatsunokuchi, Ishikawa 923-1292, Japan
7 Department of Clinical Genetics, The Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan
Tatsushi Toda, E-mail: toda{at}clgene.med.osaka-u.ac.jp
Abstract 
-dystroglycan (-DG) and certain congenital muscular dystrophies known as seconday -dystroglycanopathies (-DGpathies). Fukuyama-type congenital muscular dystrophy (FCMD) is classified as a secondary -DGpathy since the responsible gene, fukutin, is a putative glycosyltransferase for -DG. To investigate the pathophysiology of secondary -DGpathies, we profiled gene expression in skeletal muscle from FCMD patients. cDNA microarray analysis and quantitative real-time PCR showed that expression of developmentally regulated genes, including myosin heavy chain (MYH) and myogenic transcription factors (MRF4, myogenin and MyoD), in FCMD muscle fibers is inconsistent with dystrophy and active muscle regeneration, instead more of implicating maturational arrest. FCMD skeletal muscle contained mainly immature type 2C fibers positive for immature-type MYH. These characteristics are distinct from Duchenne muscular dystrophy, suggesting that another mechanism in addition to dystrophy accounts for the FCMD skeletal muscle lesion. Immunohistochemical analysis revealed morphologically aberrant neuromuscular junctions (NMJs) lacking MRF4 co-localization. Hypoglycosylated -DG indicated a lack of aggregation, and acetylcholine receptor (AChR) clustering was compromised in FCMD and the myodystrophy mouse, another model of secondary -DGpathy. Electron microscopy showed aberrant NMJs and neural terminals, as well as myotubes with maturational defects. Functional analysis of NMJs of -DGpathy showed decreased miniature endplate potential (MEPP) and higher sensitivities to d-tubocuraline, suggesting abberant or collapsed formation of NMJs. Because -DG aggregation and subsequent clustering of AChR are crucial for NMJ formation, hypoglycosylation of -DG results in aberrant NMJ formation and delayed muscle terminal maturation in secondary -DGpathies. Although severe necrotic degeneration or wasting of skeletal muscle fibers is the main cause of congenital muscular dystrophies, maturational delay of muscle fibers also underlies the etiology of secondary -DGpathies.
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