Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholinesterase / metabolism
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Aminophenols
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Animals
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Biophysics
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Diaphragm / physiopathology
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Diaphragm / ultrastructure
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Disease Models, Animal*
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Gene Expression Regulation / genetics
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Genetic Predisposition to Disease*
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Hand Strength / physiology
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Humans
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In Vitro Techniques
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Isoleucine / genetics*
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Mice
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Mice, Transgenic
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Microscopy, Electron, Transmission
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Miniature Postsynaptic Potentials / drug effects
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Miniature Postsynaptic Potentials / genetics
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Motor Endplate / physiopathology
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Motor Endplate / ultrastructure
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Mutagenesis / genetics
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Myasthenic Syndromes, Congenital / genetics*
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Myasthenic Syndromes, Congenital / pathology
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Neurofilament Proteins / metabolism
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Neuromuscular Junction / pathology
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Neuromuscular Junction / physiopathology
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Neuromuscular Junction / ultrastructure
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Patch-Clamp Techniques
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Phenylalanine / genetics*
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Receptors, Nicotinic / genetics*
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Receptors, Nicotinic / metabolism
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S100 Proteins / metabolism
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Synaptophysin / metabolism
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Time Factors
Substances
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Aminophenols
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CHRNE protein, human
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Neurofilament Proteins
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Receptors, Nicotinic
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S100 Proteins
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Synaptophysin
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neurofilament protein 150
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Isoleucine
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Phenylalanine
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glyoxal bis(2-hydroxyanil)
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Acetylcholinesterase