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.
The slow-channel syndrome is one of several congenital myasthenic syndromes that result from inherited abnormalities of the ion channel of the skeletal muscle acetylcholine receptor (AChR). The ion channel is formed by the second transmembrane domains (M2) of the four AChR subunits. We screened the genomic DNA of one family with the slow-channel syndrome for mutations in the coding sequences for the M2 domains of the four AChR subunits and report the identification of a missense mutation that causes a leucine-to-phenylalanine substitution at position 269 of the epsilon subunit in three affected members of a family with the slow-channel syndrome. We propose that this mutation may be responsible for the disease.
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