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J. Biol. Chem., Vol. 279, Issue 12, 11402-11407, March 19, 2004

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Reduction of UDP-N-acetylglucosamine 2-Epimerase/N-Acetylmannosamine Kinase Activity and Sialylation in Distal Myopathy with Rimmed Vacuoles^*

Satoru Noguchi¶, Yoko Keira, Kumiko Murayama, Megumu Ogawa, Masako Fujita, Genri Kawahara, Yasushi Oya||, Masaoki Imazawa**, Yu-ichi Goto, Yukiko K. Hayashi, Ikuya Nonaka||, and Ichizo Nishino

From the Department of Neuromuscular Research, ^**Division of Radiation Protection, Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, and ^||National Center Hospital for Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan

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.

Received for publication, December 3, 2003 , and in revised form, December 30, 2003.

^* This study was supported by a grant for research on psychiatric and neurological diseases and mental health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 81-423412712; Fax: 81-423461742; E-mail: noguchi{at}ncnp.go.jp.

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