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A β‐subunit mutation in the acetylcholine receptor channel gate causes severe slow‐channel syndrome
Author(s) -
Gomez Christopher M.,
Maselli Ricardo,
Gammack Jason,
Lasalde Jose,
Tamamizu Shiori,
Cornblath David R.,
Lehar Mohamed,
McNamee Mark,
Kuncl Ralph W.
Publication year - 1996
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.410390607
Subject(s) - acetylcholine receptor , protein subunit , mutation , channel (broadcasting) , acetylcholine , receptor , genetics , microbiology and biotechnology , biology , medicine , endocrinology , gene , computer science , telecommunications
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 β 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.