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Muscular dystrophies are a hereditary diseases characterized by progressive degeneration and necrosis of muscle fibers. Duchenne muscle dystrophy (DMD), the most common type of muscular dystrophy, causes severe and rapidly progressive muscle wasting leading to early death. The disease is usually diagnosed when children are quite young (2–5 years of age) as they exhibit a waddling gait and have frequent falls. Because the mutation that causes DMD is X-linked and recessive, its symptoms appear almost exclusively in boys, with an incidence of approximately 1 in 3000‒5000 births. Patients typically require a wheelchair by age 10–12 due to lack of ambulation and die from cardiac or respiratory failure in their 20s. Although the protein that is mutated in DMD, dystrophin, was identified more than 20 years ago, no cure for DMD is available. However, advances in medical technology have prolonged the life expectancy for patients with DMD by 5‒10 years. A commonly used animal model for DMD is the mdx mouse, which has a point mutation in exon 23 of the dystrophin gene that eliminates its expression of the gene [Bulfield, G. et al. (1984) Proc. Natl. Acad. Sci. USA 81, 1189‒1192]. Although mdx mice develop several phenotypes similar to those of human DMD, the course of their disease is much milder. For example, mdx limb muscles show significant fibrosis only when the animals are very old, and the life span of mdx mice is reduced by less than 20%. What difference between humans and mice causes this marked difference in the severity of disease development? Chandrasekharan et al. recently reported that a human-specific change in glycan expression contributes to this discrepancy [Chandrasekharan, K. et al. (2010) Sci. Transl. Med. 2, 42–54]. Within muscle t issue, a dystrophin-associated glycoprotein (DAG) complex links the basal lamina of the extracellular matrix (ECM) to the intracellular cytoskeleton, thereby stabilizing the sarcolemma membrane. In addition to dystrophin, the DAG complex contains several other proteins, including αand β-dystroglycan (DG). In the extracellular milieu, β-DG binds to α-DG; inside the cell, it binds to dystrophin, which connects the DAG complex to F-actin. α-DG also binds to laminin in the basal lamina through an O-mannosylated glycan structure (Siaα2‒3Galβ1‒4GlcNAcβ1 ‒2Man) presented on the mucin domain of the α-DG ヒトにおけるNeu5Gc 欠損がデュシェンヌ型筋ジストロフィーの重症化をもたらす

Lack of Neu5Gc Expression Contributes to the Severity of Duchenne Muscular Dystrophy in Humans