Rinsho Shinkeigaku (Clinical Neurology)

The 50th Annual Meeting of the Japanese Society of Neurology

Pathomechanism and therapeutic strategy of Fukuyama congenital muscular dystrophy and related disorders

Tatsushi Toda, M.D.

Division of Neurology, Kobe University Graduate School of Medicine

Hypoglycosylation and reduced laminin-binding activity of α-dystroglycan are common characteristics of dystroglycanopathy, which is a group of congenital and limb-girdle muscular dystrophies. We previously identified the genes for Fukuyama congenital muscular dystrophy (FCMD) and muscle-eye-brain disease (MEB). FCMD, caused by a mutation in the fukutin gene, is a severe form of dystroglycanopathy. Knock-in mice carrying the founder retrotransposal insertion exhibited hypoglycosylated α-dystroglycan; however, no signs of muscular dystrophy were observed. More sensitive methods detected minor levels of intact α-dystroglycan, and solid-phase assays determined laminin binding levels to be approximately 50% of normal. In contrast, intact α-dystroglycan is undetectable in the dystrophic Large mouse, and laminin-binding activity is markedly reduced. These data indicate that a small amount of intact α-dystroglycan is sufficient to maintain muscle cell integrity in knock-in mice, suggesting that the treatment of dystroglycanopathies might not require the full recovery of glycosylation. Transfer of fukutin into knock-in mice restored glycosylation of α-dystroglycan. Transfer of LARGE produced laminin-binding forms of α-dystroglycan in both knock-in mice and the POMGnT1 mutant mouse. These data suggest that even partial restoration of α-dystroglycan glycosylation and laminin-binding activity by replacing or augmenting glycosylation-related genes might effectively deter dystroglycanopathy progression and thus provide therapeutic benefits.
Full Text of this Article in Japanese PDF (497K)

(CLINICA NEUROL, 49: 859|862, 2009)
key words: Fukuyama congenital muscular dystrophy, fukutin, dystroglycanopathy, LARGE, sugar chain

(Received: 21-May-09)