A BETA-SUBUNIT MUTATION IN THE ACETYLCHOLINE-RECEPTOR CHANNEL GATE CAUSES SEVERE SLOW-CHANNEL SYNDROME

Point mutations in the genes encoding the acetylcholine receptor (AChR ) subunits have been recognized in some patients with slow-channel con genital myasthenic syndromes (CMS). Clinical, electrophysiological, an d pathological differences between these patients may be due to the di stinct effects of individual mutations. We report that a spontaneous m utation of the beta subunit that interrupts the leucine ring of the AC hR channel gate causes an eightfold increase in channel open time and a severe CMS characterized by severe endplate myopathy and extensive r emodeling of the postsynaptic membrane. The pronounced abnormalities i n neuromuscular synaptic architecture and function, muscle fiber damag e and weakness, resulting from a single point mutation are a dramatic example of a mutation having a dominant gain of function and of heredi tary excitotoxicity.