title: A new mouse model for the slow-channel congenital myasthenic syndrome induced by the AChR εL221F mutation.
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.
authors.affiliation: Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Chevessier
authors.forename: Christoph
authors.initials: C
authors.lastname: Peter
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mersdorf
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Girard
authors.forename: Eric
authors.initials: E
authors.lastname: Krejci
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: McArdle
authors.forename: Veit
authors.initials: V
authors.lastname: Witzemann
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000627:Aminophenols; D000818:Animals; D001703:Biophysics; D003964:Diaphragm / Q000503:physiopathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease; D018737:Hand Strength / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007532:Isoleucine / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D009045:Motor Endplate / Q000503:physiopathology / Q000648:ultrastructure; D016296:Mutagenesis / Q000235:genetics; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000473:pathology; D016900:Neurofilament Proteins / Q000378:metabolism; D009469:Neuromuscular Junction / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D010649:Phenylalanine / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D013997:Time Factors
chemical_list: D000627:Aminophenols; C504423:CHRNE protein, human; D016900:Neurofilament Proteins; D011978:Receptors, Nicotinic; D009418:S100 Proteins; D016708:Synaptophysin; C050934:neurofilament protein 150; D007532:Isoleucine; D010649:Phenylalanine; C007899:glyoxal bis(2-hydroxyanil); D000110:Acetylcholinesterase