MODE SWITCHING KINETICS PRODUCED BY A NATURALLY-OCCURRING MUTATION INTHE CYTOPLASMIC LOOP OF THE HUMAN ACETYLCHOLINE-RECEPTOR EPSILON-SUBUNIT

We describe the genetic and kinetic defects in a congenital myasthenic syndrome caused by heteroallelic mutations of the acetylcholine recep tor (AChR) epsilon subunit gene. The mutations are an in-frame duplica tion of six residues in the long cytoplasmic loop (epsilon 1254ins18) and a cysteine-loop null mutation (epsilon C128S). The epsilon 1254 in s18 mutation causes mode switching in the kinetics of receptor activat ion in which three modes activate slowly and inactivate rapidly. The e psilon 1245ins18-AChR at the endplate shows abnormally brief activatio n episodes during steady state agonist application and appears electri cally silent during the synaptic response to acetylcholine. The phenot ypic consequences are endplate AChR deficiency, simplification of the postsynaptic region, and compensatory expression of fetal AChR that re stores electrical activity at the endplate and rescues the phenotype.