MUTATION OF THE ACETYLCHOLINE-RECEPTOR ALPHA-SUBUNIT CAUSES A SLOW-CHANNEL MYASTHENIC SYNDROME BY ENHANCING AGONIST BINDING-AFFINITY

In five members of a family and another unrelated person affected by a slow-channel congenital myasthenic syndrome (SCCMS), molecular geneti c analysis of acetylcholine receptor (AChR) subunit genes revealed a h eterozygous G to A mutation at nucleotide 457 of the a subunit, conver ting codon 153 from glycine to serine (alpha G153S). Electrophysiologi c analysis of SCCMS end plates revealed prolonged decay of miniature e nd plate currents and prolonged activation episodes of single AChR cha nnels. Engineered mutant AChR expressed in HEK fibroblasts exhibited p rolonged activation episodes strikingly similar to those observed at t he SCCMS end plates. Single-channel kinetic analysis of engineered alp ha G153S 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 analys is indicated increased desensitization of the mutant AChR. Thus, ACh b inding affinity can dictate the time course of the synaptic response, and alpha G153 contributes to the low binding affinity for ACh needed to speed the decay of the synaptic response.