title: A beta-subunit mutation in the acetylcholine receptor channel gate causes severe slow-channel syndrome.
abstract: Point mutations in the genes encoding the acetylcholine receptor (AChR) subunits have been recognized in some patients with slow-channel congenital myasthenic syndromes (CMS). Clinical, electrophysiological, and pathological differences between these patients may be due to the distinct effects of individual mutations. We report that a spontaneous mutation of the beta subunit that interrupts the leucine ring of the AChR channel gate causes an eightfold increase in channel open time and a severe CMS characterized by severe endplate myopathy and extensive remodeling of the postsynaptic membrane. The pronounced abnormalities in neuromuscular synaptic architecture and function, muscle fiber damage and weakness, resulting from a single point mutation are a dramatic example of a mutation having a dominant gain of function and of hereditary excitotoxicity.
authors.affiliation: Department of Neurology, University of Minnesota, Minneapolis, 54555, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Gomez
authors.forename: R
authors.initials: R
authors.lastname: Maselli
authors.forename: J
authors.initials: J
authors.lastname: Gammack
authors.forename: J
authors.initials: J
authors.lastname: Lasalde
authors.forename: S
authors.initials: S
authors.lastname: Tamamizu
authors.forename: D R
authors.initials: DR
authors.lastname: Cornblath
authors.forename: M
authors.initials: M
authors.lastname: Lehar
authors.forename: M
authors.initials: M
authors.lastname: McNamee
authors.forename: R W
authors.initials: RW
authors.lastname: Kuncl
mesh_terms: D000328:Adult; D000483:Alleles; D001483:Base Sequence; D001665:Binding Sites; D003062:Codon / Q000502:physiology; D004576:Electromyography; D005784:Gene Amplification; D016678:Genome; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D018485:Muscle Fibers, Skeletal / Q000648:ultrastructure; D009157:Myasthenia Gravis / Q000175:diagnosis* / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics; D011950:Receptors, Cholinergic / Q000235:genetics*; D013570:Synaptic Membranes / Q000235:genetics / Q000648:ultrastructure; D013577:Syndrome
chemical_list: D003062:Codon; D011950:Receptors, Cholinergic