Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor ε subunit

We describe the genetic and kinetic defects for a low-affinity fast channel disease of the acetylcholine receptor (AChR) that causes a myasthenic syndrome. In two unrelated patients with very small miniature end plate (EP) potentials, but with normal EP AChR density and normal EP ultrastructure, patch-clamp studies demonstrated infrequent AChR channel events, diminished channel reopenings during ACh occupancy, and resistance to desensitization by ACh. Each patient had two heteroallelic AChR ε subunit gene mutations: a common εP121L mutation, a signal peptide mutation (εG-8R) (patient 1), and a glycosylation consensus site mutation (εS143L) (patient 2). AChR expression in HEK fibroblasts was normal with εP121L but was markedly reduced with the other mutations. Therefore, εP121L defines the clinical phenotype. Studies of the engineered EP121L AChR revealed a markedly decreased rate of channel opening, little change in affinity of the resting state for ACh, but reduced affinity of the open channel and desensitized states.