Neuromuscular junction abnormalities in DNM2-related centronuclear myopathy

J Mol Med (Berl). 2013 Jun;91(6):727-37. doi: 10.1007/s00109-013-0994-4. Epub 2013 Jan 22.

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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Child
  • Cholinesterase Inhibitors / therapeutic use
  • Disease Models, Animal
  • Dynamin II / physiology*
  • Female
  • Humans
  • Male
  • Motor Activity / drug effects
  • Muscle Weakness
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / ultrastructure
  • Myopathies, Structural, Congenital / drug therapy
  • Myopathies, Structural, Congenital / pathology
  • Myopathies, Structural, Congenital / physiopathology*
  • Neuromuscular Junction / physiopathology*
  • Pyridostigmine Bromide / therapeutic use
  • Young Adult
  • Zebrafish

Substances

  • Cholinesterase Inhibitors
  • Dynamin II
  • Pyridostigmine Bromide