TY - JOUR
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
AU - Milone, Margherita
AU - Wang, Hai Long
AU - Ohno, Kinji
AU - Fukudome, Takayasu
AU - Pruitt, J. Ned
AU - Bren, Nina
AU - Sine, Steven M.
AU - Engel, Andrew G.
PY - 1997/8/1
Y1 - 1997/8/1
N2 - 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.
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.
KW - Acetylcholine receptor α subunit gene
KW - Agonist binding affinity
KW - Desensitization
KW - Endplate myopathy
KW - Mutation analysis
KW - Neuromuscular transmission
KW - Single-channel recording
KW - Slow-channel congenital myasthenic syndrome
UR - http://www.scopus.com/inward/record.url?scp=0030757151&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030757151&partnerID=8YFLogxK
U2 - 10.1523/jneurosci.17-15-05651.1997
DO - 10.1523/jneurosci.17-15-05651.1997
M3 - Article
C2 - 9221765
AN - SCOPUS:0030757151
SN - 0270-6474
VL - 17
SP - 5651
EP - 5665
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 15
ER -