Neurobiology of Disease 2012-03-01

A new mouse model for the slow-channel congenital myasthenic syndrome induced by the AChR εL221F mutation.

Frédéric Chevessier, Christoph Peter, Ulrike Mersdorf, Emmanuelle Girard, Eric Krejci, Joseph J McArdle, Veit Witzemann

文献索引：Neurobiol. Dis. 45(3) , 851-61, (2012)

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摘要

We have generated a new mouse model for congenital myasthenic syndromes by inserting the missense mutation L221F into the ε 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 remodeling 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 signaling pathways induced by excitotoxicity at peripheral synapses.Copyright © 2011 Elsevier Inc. All rights reserved.