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

Christopher M. Gomez, Ricardo A Maselli, Jason Gammack, Jose Lasalde, Shiori Tamamizu, David R. Cornblath, Mohamed Lehar, Mark McNamee, Ralph W. Kuncl

Research output: Contribution to journalArticlepeer-review

90 Scopus citations

Abstract

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 β subunit that interrupts the leucine ring of the AChR channel gate causes an eighffold 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.

Original languageEnglish (US)
Pages (from-to)712-723
Number of pages12
JournalAnnals of Neurology
Volume39
Issue number6
DOIs
StatePublished - Jun 1996

ASJC Scopus subject areas

  • Neuroscience(all)

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