title: Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor epsilon subunit.
abstract: 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 epsilon subunit gene mutations: a common epsilon P121L mutation, a signal peptide mutation (epsilon G-8R) (patient 1), and a glycosylation consensus site mutation (epsilon S143L) (patient 2). AChR expression 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 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.
authors: Muscle Research Laboratory, Department of Neurology, Mayo Foundation, Rochester, Minnesota 55905, USA.
authors: K
authors: K
authors: Ohno
authors: H L
authors: HL
authors: Wang
authors: M
authors: M
authors: Milone
authors: N
authors: N
authors: Bren
authors: J M
authors: JM
authors: Brengman
authors: S
authors: S
authors: Nakano
authors: P
authors: P
authors: Quiram
authors: J N
authors: JN
authors: Pruitt
authors: S M
authors: SM
authors: Sine
authors: A G
authors: AG
authors: Engel
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000595:Amino Acid Sequence; D001483:Base Sequence; D001667:Binding, Competitive; D002460:Cell Line; D004594:Electrophysiology; D006801:Humans; D007700:Kinetics; D015624:Lambert-Eaton Myasthenic Syndrome / Q000151:congenital / Q000235:genetics* / Q000503:physiopathology; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D018408:Patch-Clamp Techniques; D011950:Receptors, Cholinergic / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
chemical_list: D015335:Molecular Probes; D011950:Receptors, Cholinergic; D000109:Acetylcholine