Slow-channel myasthenie syndrome caused by enhanced activation and agonist binding affinity due to mutation in the M2 domain of the ACHR α subunit

We describe a novel genetic and kinetic defect in a slowchannel congenital myasthénie syndrome. A 12-year-old boy had severe myasthénie symptoms since birth, 45-60% EMG decrement, repetitive compound muscle action potential, no anti-AChR antibodies, and no similarly affected relatives. He had a severe endplate myopathy causing loss of AChR, long and biexponentially decaying endplate currents, and markedly prolonged opening episodes of single AChR channels. Genetic analysis showed a heterozygous V249F mutation in the a-M2 channel pore domain in the patient and mosaicism for ctV249F in his asymptomatic father. Expression studies in HEK cells revealed prolonged channel openings, increased conductance, increased affinity for ACh, openings in the absence of ACh, and enhanced desehsitization. Neuromuscular transmission is compromised by cationic overloading, loss of AChR, partial AChR desensitization in the resting state, and depolarization block on activity from staircase summation of prolonged endplate potentials.