Slow-channel myasthenic syndrome caused by enhanced activation, desensitization, and agonist binding affinity attributable to mutation in the M2 domain of the acetylcholine receptor α subunit

Margherita Milone, Hai Long Wang, Kinji Ohno, Takayasu Fukudome, J. Ned Pruitt, Nina Bren, Steven M. Sine, Andrew G. Engel

Research output: Contribution to journalArticle

113 Scopus citations

Abstract

We describe a novel genetic and kinetic defect in a slow-channel congenital myasthenic syndrome. The severely disabled propositus has advanced endplate myopathy, prolonged and biexponentially decaying endplate currents, and prolonged acetylcholine receptor (AChR) channel openings. Genetic analysis reveals the heterozygous mutation αV249F in the propositus and mosaicism for αV249F in the asymptomatic father. Unlike mutations described previously in the M2 transmembrane domain, αV249F is located N-terminal to the conserved leucines and is not predicted to face the channel lumen. Expression of the αV249F AChR in HEK fibroblasts demonstrates increased channel openings in the absence of ACh, prolonged openings in its presence, enhanced steady-state desensitization, and nanomolar rather than micromolar affinity of one of the two binding sites in the resting activatable state. Thus, neuromuscular transmission is compromised because cationic overloading leads to degenerating junctional folds and loss of AChR, because an increased fraction of AChR is desensitized in the resting state, and because physiological rates of stimulation elicit additional desensitization and depolarization block of transmission.

Original languageEnglish (US)
Pages (from-to)5651-5665
Number of pages15
JournalJournal of Neuroscience
Volume17
Issue number15
DOIs
StatePublished - Aug 1 1997
Externally publishedYes

Keywords

  • Acetylcholine receptor α subunit gene
  • Agonist binding affinity
  • Desensitization
  • Endplate myopathy
  • Mutation analysis
  • Neuromuscular transmission
  • Single-channel recording
  • Slow-channel congenital myasthenic syndrome

ASJC Scopus subject areas

  • Neuroscience(all)

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