Mode switching kinetics produced by a naturally occurring mutation in the cytoplasmic loop of the human acetylcholine receptor ε subunit

We describe the genetic and kinetic defects in a congenital myasthenic syndrome caused by heteroallelic mutations of the acetylcholine receptor (AChR) ε subunit gene. The mutations are an in-frame duplication of six residues in the long cytoplasmic loop (ε1254ins18) and a cysteine-loop null mutation (εC128S). The ε1254 ins18 mutation causes mode switching in the kinetics of receptor activation in which three modes activate slowly and inactivate rapidly. The ε1245ins18-AChR at the endplate shows abnormally brief activation episodes during steady state agonist application and appears electrically silent during the synaptic response to acetylcholine. The phenotypic consequences are endplate AChR deficiency, simplification of the post-synaptic region, and compensatory expression of fetal AChR that restores electrical activity at the endplate and rescues the phenotype.