Human Molecular Genetics Advance Access originally published online on January 19, 2009
Human Molecular Genetics 2009 18(7):1353-1367; doi:10.1093/hmg/ddp036
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Deficiency of the E3 ubiquitin ligase TRIM32 in mice leads to a myopathy with a neurogenic component
Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, 635 Charles E. Young Dr South, CA 90095-7334, USA
* To whom correspondence should be addressed. Tel: +1 310 794 5225; Fax: +1 310 206 1998; Email: mspencer{at}mednet.ucla.edu
Received October 22, 2008; Accepted January 16, 2009
Limb-girdle muscular dystrophy type 2H (LGMD2H) and sarcotubular myopathy are hereditary skeletal muscle disorders caused by mutations in TRIM32. We previously identified TRIM32 as an E3 ubiquitin ligase that binds to myosin and ubiquitinates actin. To date four TRIM32 mutations have been linked to LGMD2H, all of which occur in the C-terminal NHL domains. Unexpectedly, a fifth mutation in the B-box of TRIM32 causes a completely different, multisystemic disorder, Bardet–Biedl syndrome type 11. It is not understood how allelic mutations in TRIM32 can create such diverse phenotypic outcomes. To generate a tool for elucidating the complex in vivo functions of TRIM32, we created the first murine Trim32 knock-out model (T32KO). Histological analysis of T32KO skeletal muscles revealed mild myopathic changes. Electron microscopy showed areas with Z-line streaming and a dilated sarcotubular system with vacuoles—the latter being a prominent feature of sarcotubular myopathy. Therefore, our model replicates phenotypes of LGMD2H and sarcotubular myopathy. The level of Trim32 expression in normal mouse brain exceeds that observed in skeletal muscle by more than 100 times, as we demonstrated by real-time PCR. Intriguingly, analysis of T32KO neural tissue revealed a decreased concentration of neurofilaments and a reduction in myelinated motoraxon diameters. The axonal changes suggest a shift toward a slower motor unit type. Not surprisingly, T32KO soleus muscle expressed an elevated type I slow myosin isotype with a concomitant reduction in the type II fast myosin. These data suggest that muscular dystrophy due to TRIM32 mutations involves both neurogenic and myogenic characteristics.
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  M. Locke, C. L. Tinsley, M. A. Benson, and D. J. Blake TRIM32 is an E3 ubiquitin ligase for dysbindin Hum. Mol. Genet., July 1, 2009; 18(13): 2344 - 2358. [Abstract] [Full Text] [PDF]
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