RT Journal Article
SR Electronic
T1 Slow-Channel Myasthenic Syndrome Caused By Enhanced Activation, Desensitization, and Agonist Binding Affinity Attributable to Mutation in the M2 Domain of the Acetylcholine Receptor α Subunit
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 5651
OP 5665
DO 10.1523/JNEUROSCI.17-15-05651.1997
VO 17
IS 15
A1 Margherita Milone
A1 Hai-Long Wang
A1 Kinji Ohno
A1 Takayasu Fukudome
A1 J. Ned Pruitt
A1 Nina Bren
A1 Steven M. Sine
A1 Andrew G. Engel
YR 1997
UL http://www.jneurosci.org/content/17/15/5651.abstract
AB We describe a novel genetic and kinetic defect in a slow-channel congenital myasthenic syndrome. The severely disabled propositus has advanced endplate myopathy, prolonged and biexponentially decaying endplate currents, and prolonged acetylcholine receptor (AChR) channel openings. Genetic analysis reveals the heterozygous mutation αV249F in the propositus and mosaicism for αV249F in the asymptomatic father. Unlike mutations described previously in the M2 transmembrane domain, αV249F is located N-terminal to the conserved leucines and is not predicted to face the channel lumen. Expression of the αV249F AChR in HEK fibroblasts demonstrates increased channel openings in the absence of ACh, prolonged openings in its presence, enhanced steady-state desensitization, and nanomolar rather than micromolar affinity of one of the two binding sites in the resting activatable state. Thus, neuromuscular transmission is compromised because cationic overloading leads to degenerating junctional folds and loss of AChR, because an increased fraction of AChR is desensitized in the resting state, and because physiological rates of stimulation elicit additional desensitization and depolarization block of transmission.