slow-channel myasthenic syndrome mutant eL221F, inferred from maximum likelihood fits

The discovery of the genetic basis for many of the human congenital myasthenic syndromes (Engel et al. 1999; Beeson & Newsom-Davis, 2000) has added to the inherent interest in investigation of the relationship between structure and function in the nicotinic acetylcholine receptor (AChR) of the muscle endplate. The slow channel congenital myasthenic syndromes result from single amino acid ‘gain-of-function’ mutations in the receptor protein that give rise to prolonged endplate currents. Muscle weakness is thought to result from endplate damage caused by excess calcium entry. In addition, at physiological rates of stimulation the prolonged endplate potentials summate, leading to persistent depolarisation at the endplate and the consequent inactivation of the voltage-gated sodium channels.