CONGENITAL MYASTHENIC SYNDROME CAUSED BY DECREASED AGONIST BINDING-AFFINITY DUE TO A MUTATION IN THE ACETYLCHOLINE-RECEPTOR EPSILON-SUBUNIT

We describe the genetic and kinetic defects for a low-affinity fast ch annel disease of the acetylcholine receptor (AChR) that causes a myast henic syndrome. In two unrelated patients with very small miniature en d plate (EP) potentials, but with normal EP AChR density and normal EP ultrastructure, patch-clamp studies demonstrated infrequent AChR chan nel events, diminished channel reopenings during ACh occupancy, and re sistance to desensitization by ACh. Each patient had two heteroallelic AChR epsilon subunit gene mutations: a common epsilon P121L mutation, a signal peptide mutation (epsilon G-8R) (patient 1), and a glycosyla tion consensus site mutation (epsilon S143L) (patient 2). AChR express ion in HEK fibroblasts was normal with epsilon P121L but was markedly reduced with the other mutations. Therefore, epsilon P121L defines the clinical phenotype. Studies of the engineered epsilon P121L AChR reve aled a markedly decreased rate of channel opening, little change in af finity of the resting state for ACh, but reduced affinity of the open channel and desensitized states.