Human Molecular Genetics Advance Access published online on December 12, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl446
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© The Author 2006. Published by Oxford University Press. All rights reserved
A Gne knockout mouse expressing human V572L mutation develops features similar to distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, Japan
* To whom correspondence should be addressed. 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo, Japan, 187-8502; Tel: +81 423461712; Fax: +81 423461742; E-mail: noguchi{at}ncnp.go.jp
Received October 3, 2006; Revised November 21, 2006; Accepted November 21, 2006
Distal myopathy with rimmed vacuoles (DMRV) or hereditary inclusion myopathy (h-IBM) is an early adult-onset distal myopathy caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/ N-acetylmannosamine kinase (GNE) gene which encodes for a bifunctional enzyme involved in sialic acid biosynthesis. It is pathologically characterized by the presence of rimmed vacuoles especially in atrophic fibers, which also occasionally contain congophilic materials that are immunoreactive to ß-amyloid, lysosomal proteins, ubiquitin, and tau proteins. To elucidate the pathomechanism of this myopathy and to explore treatment options, we generated a mouse model of DMRV/h-IBM. We knocked out the Gne gene in mouse but this resulted to embryonic lethality. We therefore generated a transgenic mouse that expressed the human GNE V572L mutation, which is the most prevalent among Japanese DMRV patients, and crossed this with Gne(+/-) mouse to obtain Gne(-/-)hGNEV572L-Tg. Interestingly, these mice exhibit marked hyposialylation in serum, muscle, and other organs. Reduction in motor performance in these mice can only be seen from 30 weeks of age. A compelling finding is the development of ß-amyloid deposition in myofibers by 32 weeks, which clearly precedes rimmed vacuole formation at 42 weeks. These results show that the Gne(-/-)hGNEV572L-Tg mouse mimics the clinical, histopathological, and biochemical features of DMRV/h-IBM, making it useful forunderstanding the pathomechanism of this myopathy and for employing different strategies for therapy. Our findings underscore the notion that hyposialylation plays an important role in the pathomechanism of DMRV/h-IBM.?
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