New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome

Andrew G. Engel, Kinji Ohno, Margherita Milone, Hai Long Wang, Satoshi Nakano, Cecilia Bouzat, J. Ned Pruitt, David O. Hutchinson, Joan M. Brengman, Nina Bren, Joern P. Sieb, Steven M. Sine

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173 Scopus citations


Mutations in genes encoding the ε, δ, β and α subunits of the end plate acetylcholine (ACh) receptor (AChR) are described and functionally characterized in three slow-channel congenital myasthenic syndrome patients. All three had prolonged end plate currents and AChR channel opening episodes and an end plate myopathy with loss of AChR from degenerating junctional folds. Genetic analysis revealed heterozygous mutations: εL269F and δQ267E in Patient 1, βV266M in Patient 2, and αN217K in Patient 3 that were not detected in 100 normal controls. Patients 1 and 2 have no similarly affected relatives; in Patient 3, the mutation cosegregates with the disease in three generations, εL269F, δQ267E and βV266M occur in the second and αN217K in the first transmembrane domain of AChR subunits; all have been postulated to contribute to the lining of the upper half of the channel lumen and all but δQ267E are positioned toward the channel lumen, and introduce an enlarged side chain. Expression studies in HEK cells indicate that all of the mutations express normal amounts of AChR, εL269F, βV266M, and αN217K slow the rate of channel closure in the presence of ACh and increase apparent affinity for ACh; εL269F and αN217K enhance desensitization, and εL269F and βV266M cause pathologic channel openings in the absence of ACh, rendering the channel leaky, δQ267E has none of these effects and is therefore a rare polymorphism or a benign mutation. The end plate myopathy stems from cationic overloading of the postsynaptic region. The safety margin of neuromuscular transmission is compromised by AChR loss from the junctional folds and by a depolarization block owing to temporal summation of prolonged end plate potentials at physiologic rates of stimulation.

Original languageEnglish (US)
Pages (from-to)1217-1227
Number of pages11
JournalHuman molecular genetics
Issue number9
StatePublished - Sep 1996

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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