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Neuromuscular Junction, Slow Channel Congenital Myasthenic Syndrome, Acetylcholine Receptor, mouse model, homologous recombination
Abstract:
We have generated a new mouse model for congenital myasthenic syndromes by inserting the
missense mutation L221F into the ? subunit of the acetylcholine receptor by homologous
recombination. This mutation has been identified in man to cause a mild form of slow−channel
congenital myasthenic syndrome with variable penetrance. In our mouse model we observe as
in human patients prolonged endplate currents. The summation of endplate potentials may
account for a depolarization block at increasing stimulus frequencies, moderate reduced
muscle strength and tetanic fade. Calcium and intracellular vesicle accumulation as well as
junctional fold loss and organelle degeneration underlying a typical endplate myopathy, were
identified. Moreover, a remodelling of neuromuscular junctions occurs in a muscle−dependent
pattern expressing variable phenotypic effects. Altogether, this mouse model provides new
insight into the pathophysiology of congenital myasthenia and serves as a new tool for
deciphering signalling pathways induced by excitotoxicity at peripheral synapses.
Key words: Neuromuscular Junction, Slow Channel Congenital Myasthenic Syndrome,
Acetylcholine Receptor, mouse model, homologous recombination
