A beta-subunit mutation in the acetylcholine receptor channel gate causes severe slow-channel syndrome

Ann Neurol. 1996 Jun;39(6):712-23. doi: 10.1002/ana.410390607.


Point mutations in the genes encoding the acetylcholine receptor (AChR) subunits have been recognized in some patients with slow-channel congenital myasthenic syndromes (CMS). Clinical, electrophysiological, and pathological differences between these patients may be due to the distinct effects of individual mutations. We report that a spontaneous mutation of the beta subunit that interrupts the leucine ring of the AChR channel gate causes an eightfold increase in channel open time and a severe CMS characterized by severe endplate myopathy and extensive remodeling of the postsynaptic membrane. The pronounced abnormalities in neuromuscular synaptic architecture and function, muscle fiber damage and weakness, resulting from a single point mutation are a dramatic example of a mutation having a dominant gain of function and of hereditary excitotoxicity.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Alleles
  • Base Sequence
  • Binding Sites
  • Codon / physiology
  • Electromyography
  • Gene Amplification
  • Genome
  • Humans
  • Ion Channel Gating / genetics*
  • Male
  • Molecular Sequence Data
  • Muscle Fibers, Skeletal / ultrastructure
  • Myasthenia Gravis / diagnosis*
  • Myasthenia Gravis / genetics*
  • Point Mutation*
  • Polymerase Chain Reaction
  • Polymorphism, Genetic / genetics
  • Receptors, Cholinergic / genetics*
  • Synaptic Membranes / genetics
  • Synaptic Membranes / ultrastructure
  • Syndrome


  • Codon
  • Receptors, Cholinergic