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 β -amyloid, lysosomal proteins, ubiquitin and tau proteins. To elucidate the pathomechanism of this myopathy and to explore the treatment options, we generated a mouse model of DMRV/h-IBM. We knocked out the Gne gene in the mouse, but this resulted in 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^(−/−) h GNE V572L-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 β -amyloid deposition in myofibers by 32 weeks, which clearly precedes rimmed vacuole formation at 42 weeks. These results show that the Gne^(−/−) h GNE V572L-Tg mouse mimics the clinical, histopathological and biochemical features of DMRV/h-IBM, making it useful for understanding 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.