A new mouse model for the slow-channel congenital myasthenic syndrome induced by the AChR εL221F mutation

Neurobiol Dis. 2012 Mar;45(3):851-61. doi: 10.1016/j.nbd.2011.10.024. Epub 2011 Dec 8.

Abstract

We have generated a new mouse model for congenital myasthenic syndromes by inserting the missense mutation L221F into the ε subunit of the acetylcholine receptor by homologous recombination. This mutation has been identified in man to cause a mild form of slow-channel congenital myasthenic syndrome with variable penetrance. In our mouse model we observe as in human patients prolonged endplate currents. The summation of endplate potentials may account for a depolarization block at increasing stimulus frequencies, moderate reduced muscle strength and tetanic fade. Calcium and intracellular vesicle accumulation as well as junctional fold loss and organelle degeneration underlying a typical endplate myopathy, were identified. Moreover, a remodeling of neuromuscular junctions occurs in a muscle-dependent pattern expressing variable phenotypic effects. Altogether, this mouse model provides new insight into the pathophysiology of congenital myasthenia and serves as a new tool for deciphering signaling pathways induced by excitotoxicity at peripheral synapses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Aminophenols
  • Animals
  • Biophysics
  • Diaphragm / physiopathology
  • Diaphragm / ultrastructure
  • Disease Models, Animal*
  • Gene Expression Regulation / genetics
  • Genetic Predisposition to Disease*
  • Hand Strength / physiology
  • Humans
  • In Vitro Techniques
  • Isoleucine / genetics*
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Miniature Postsynaptic Potentials / drug effects
  • Miniature Postsynaptic Potentials / genetics
  • Motor Endplate / physiopathology
  • Motor Endplate / ultrastructure
  • Mutagenesis / genetics
  • Myasthenic Syndromes, Congenital / genetics*
  • Myasthenic Syndromes, Congenital / pathology
  • Neurofilament Proteins / metabolism
  • Neuromuscular Junction / pathology
  • Neuromuscular Junction / physiopathology
  • Neuromuscular Junction / ultrastructure
  • Patch-Clamp Techniques
  • Phenylalanine / genetics*
  • Receptors, Nicotinic / genetics*
  • Receptors, Nicotinic / metabolism
  • S100 Proteins / metabolism
  • Synaptophysin / metabolism
  • Time Factors

Substances

  • Aminophenols
  • CHRNE protein, human
  • Neurofilament Proteins
  • Receptors, Nicotinic
  • S100 Proteins
  • Synaptophysin
  • neurofilament protein 150
  • Isoleucine
  • Phenylalanine
  • glyoxal bis(2-hydroxyanil)
  • Acetylcholinesterase