Molecular basis of congenital myasthenic syndromes: Mutations in the acetylcholine receptor

Andrew G. Engel, Kinji Ohno, Hai Long Wang, Margherita Milone, Steven M. Sine

Research output: Contribution to journalReview articlepeer-review

22 Scopus citations


The congenital myasthenic syndromes include end-plate (EP) acetylcholinesterase deficiency, presynaptic abnormalities affecting the evoked release or size of transmitter quanta, and acetylcholine (ACh) receptor (AChR) channelopathies stemming from a kinetic abnormality and/or deficiency of AChR. A kinetic abnormality predicts, and AChR deficiency may predict, one or more mutations in an AChR subunit gene. These clues have led to the identification of 53 mutations in different subunits of AChR in 55 kinships of the congenital myasthenic syndromes. The mutations either increase or decrease the response to ACh, produce AChR deficiency, or both. In the slow-channel syndromes, prolonged opening episodes of AChR cause cationic overloading of the EP and an EP myopathy; the mutations occur in different subunits and different domains of the subunits and have dominant positive effects. The M1 and M2 mutations slow channel closure, increase apparent affinity for ACh, and variably enhance desensitization, and the extracellular αG153S enhances affinity for ACh, promoting reopening of the diliganded receptor. In the low-affinity fast-channel syndrome, εP121L reduces affinity for ACh and reopening of the diliganded receptor, resulting in a decreased response to ACh and shorter burst durations. Severe EP AChR deficiency results from heterozygous or homozygous mutations that terminate translation prematurely; these are concentrated in the ε subunit, probably because substitution of the fetal γ for the adult ε subunit can rescue the phenotype from fatal null mutations in ε. Variable AChR deficiency and variable functional abnormalities stem from heteroallelic nonsense and missense mutations in AChR subunit genes.

Original languageEnglish (US)
Pages (from-to)185-194
Number of pages10
Issue number3
StatePublished - May 1 1998


  • Acetylcholine receptor
  • Congenital myasthenic syndromes
  • Mutation analysis
  • Neuromuscular junction
  • Patch-clamp analysis

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology


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