臨床神経学

第50回日本神経学会総会

<シンポジウム5―3>難治性筋疾患の病態機序―CK発見から50年―治療の時代へ
福山型筋ジストロフィーおよび類縁疾患の病態・治療戦略

戸田 達史

神戸大学大学院医学研究科神経内科学〔〒650-0017 神戸市中央区楠町7-5-1〕

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)

(臨床神経, 49:859−862, 2009)
key words:福山型筋ジストロフィー, フクチン, ジストログリカノパチー, LARGE, 糖鎖

(受付日:2009年5月21日)