Reduction of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase activity and sialylation in distal myopathy with rimmed vacuoles.
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.
Noguchi
Satoru
S
Department of Neuromuscular Research, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan. noguchi@ncnp.go.jp
Keira
Yoko
Y
Murayama
Kumiko
K
Ogawa
Megumu
M
Fujita
Masako
M
Kawahara
Genri
G
Oya
Yasushi
Y
Imazawa
Masaoki
M
Goto
Yu-Ichi
Y
Hayashi
Yukiko K
YK
Nonaka
Ikuya
I
Nishino
Ichizo
I
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*
D001704:Biopolymers; D009097:Multienzyme Complexes; C482901:UDP-N-acetylglucosamine 2-epimerase - N-acetylmannosamine kinase; D019158:N-Acetylneuraminic Acid