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Neuromuscular junction abnormalities in DNM2-related centronuclear myopathy

Abstract

Dynamin-2-related centronuclear myopathy (DNM2-CNM) is a clinically heterogeneous muscle disorder characterized by muscle weakness and centralized nuclei on biopsy. There is little known about the muscle dysfunction underlying this disorder, and there are currently no treatments. In this study, we establish a novel zebrafish model for DNM2-CNM by transiently overexpressing a mutant version of DNM2 (DNM2-S619L) during development. We show that overexpression of DNM2-S619L leads to pathological changes in muscle and a severe motor phenotype. We further demonstrate that the muscle weakness seen in these animals can be significantly alleviated by treatment with an acetylcholinesterase inhibitor. Based on these results, we reviewed the clinical history of five patients with two different DNM2-CNM mutations (S619L and E368K) and found electrophysiological evidence of abnormal neuromuscular transmission in two of the individuals. All five patients showed improved muscle strength and motor function, and/or reduced fatigability following acetylcholinesterase inhibitor treatment. Together, our results suggest that deficits at the neuromuscular junction may play an important role in the pathogenesis of DNM2-CNM and that treatments targeting this dysfunction can provide an effective therapy for patients with this disorder.

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Acknowledgments

The authors wish to thank Angela Busta and Arden Trickey Glassman for technical help with the zebrafish experimentation. They also thank Dr. Jim Teener for assistance with the neurodiagnostic assessment of the patients. This work was supported by funds from the Program for Neurological Research and Discovery and the A. Alfred Taubman Medical Research Institute. EMG was supported by a Walbridge Aldinger Graduate Fellowship. This work was additionally supported by the National Institutes of Health [1K08AR054835 to JJD] and the Australian National Health and Medical Research Council [grants 1022707, 1031893 and 1035828 to NFC].

Conflict of interest

The authors declare no conflict of interest in connection with the submitted material.

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Correspondence to James J. Dowling.

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Gibbs, E.M., Clarke, N.F., Rose, K. et al. Neuromuscular junction abnormalities in DNM2-related centronuclear myopathy. J Mol Med 91, 727–737 (2013) doi:10.1007/s00109-013-0994-4

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Keywords

  • Dynamin-2
  • Myopathy
  • Neuromuscular junction
  • Acetylcholinesterase inhibitor