title: Reduction of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase activity and sialylation in distal myopathy with rimmed vacuoles.
abstract: Distal myopathy with rimmed vacuoles is an autosomal recessive muscle disease with preferential involvement of the tibialis anterior that spares the quadriceps muscles in young adulthood. In a Japanese patient with distal myopathy with rimmed vacuoles, we identified pathogenic mutations in the gene encoding the bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase, which catalyzes the initial two steps in the biosynthesis of sialic acid. In this study, we demonstrated the relationship between the genetic mutations and enzymatic activities using an in vitro expression assay system. Furthermore, we also showed that the levels of sialic acid in muscle and primary cultured cells from DMRV patients were reduced to 60-75% of control. The reactivities to lectins were also variable in some myofibers, suggesting that hyposialylation and abnormal glycosylation in muscles may contribute to the focal accumulations of autophagic vacuoles, amyloid deposits, or both in patient muscle tissue. The addition of ManNAc and NeuAc to primary cultured cells normalized sialylation levels, thus demonstrating the therapeutic potential of these compounds for this disease.
authors.affiliation: Department of Neuromuscular Research, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan. noguchi@ncnp.go.jp
authors.forename: Satoru
authors.initials: S
authors.lastname: Noguchi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Keira
authors.forename: Kumiko
authors.initials: K
authors.lastname: Murayama
authors.forename: Megumu
authors.initials: M
authors.lastname: Ogawa
authors.forename: Masako
authors.initials: M
authors.lastname: Fujita
authors.forename: Genri
authors.initials: G
authors.lastname: Kawahara
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Oya
authors.forename: Masaoki
authors.initials: M
authors.lastname: Imazawa
authors.forename: Yu-Ichi
authors.initials: Y
authors.lastname: Goto
authors.forename: Yukiko K
authors.initials: YK
authors.lastname: Hayashi
authors.forename: Ikuya
authors.initials: I
authors.lastname: Nonaka
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
mesh_terms: D000818:Animals; D001704:Biopolymers; D019556:COS Cells; D016022:Case-Control Studies; D006801:Humans; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000201:enzymology* / Q000378:metabolism; D009154:Mutation; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D014617:Vacuoles / Q000648:ultrastructure*
chemical_list: D001704:Biopolymers; D009097:Multienzyme Complexes; C482901:UDP-N-acetylglucosamine 2-epimerase - N-acetylmannosamine kinase; D019158:N-Acetylneuraminic Acid