Mutation of the acetylcholine receptor α subunit causes a slow-channel myasthenic syndrome by enhancing agonist binding affinity

Steven M. Sine, Kinji Ohno, Cecilia Bouzat, Anthony Auerbach, Margherita Milone, Jerry N Pruitt, Andrew G. Engel

Research output: Contribution to journalArticle

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Abstract

In five members of a family and another unrelated person affected by a slow-channel congenital myasthenic syndrome (SCCMS), molecular genetic analysis of acetylcholine receptor (AChR) subunit genes revealed a heterozygous G to A mutation at nucleotide 457 of the α subunit, converting codon 153 from glycine to serine (αG153S). Electrophysiologic analysis of SCCMS end plates revealed prolonged decay of miniature end plate currents and prolonged activation episodes of single AChR channels. Engineered mutant AChR expressed in HEK fibroblasts exhibited prolonged activation episodes strikingly similar to those observed at the SCCMS end plates. Single-channel kinetic analysis of engineered αG153S AChR revealed a markedly decreased rate of ACh dissociation, which causes the mutant AChR to open repeatedly during ACh occupancy. In addition, ACh binding measurements combined with the kinetic analysis indicated increased desensitization of the mutant AChR. Thus, ACh binding affinity can dictate the time course of the synaptic response, and αG153 contributes to the low binding affinity for ACh needed to speed the decay of the synaptic response.

Original languageEnglish (US)
Pages (from-to)229-239
Number of pages11
JournalNeuron
Volume15
Issue number1
DOIs
StatePublished - Jan 1 1995
Externally publishedYes

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Muscle Weakness
Cholinergic Receptors
Congenital Myasthenic Syndromes
Mutation
Codon
Glycine
Serine
Molecular Biology
Nucleotides
Fibroblasts
Genes

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Mutation of the acetylcholine receptor α subunit causes a slow-channel myasthenic syndrome by enhancing agonist binding affinity. / Sine, Steven M.; Ohno, Kinji; Bouzat, Cecilia; Auerbach, Anthony; Milone, Margherita; Pruitt, Jerry N; Engel, Andrew G.

In: Neuron, Vol. 15, No. 1, 01.01.1995, p. 229-239.

Research output: Contribution to journalArticle

Sine, Steven M. ; Ohno, Kinji ; Bouzat, Cecilia ; Auerbach, Anthony ; Milone, Margherita ; Pruitt, Jerry N ; Engel, Andrew G. / Mutation of the acetylcholine receptor α subunit causes a slow-channel myasthenic syndrome by enhancing agonist binding affinity. In: Neuron. 1995 ; Vol. 15, No. 1. pp. 229-239.
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