Analysis Tools
behavior/neurological
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• by around 5 months of age, mutants show less spontaneous exploratory activity
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homeostasis/metabolism
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• mutants are more susceptible to fatal complications during pentobarbital anesthesia than controls
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respiratory system
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• mutants exhibit a faster respiratory rate by 6-8 weeks of age
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muscle
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• muscle fiber endplate regions of 2-4 month old mutants show increased eosinophilic staining suggesting localized hypercontracture
• mutants older than 4 months of age exhibit scattered angulated or atrophic fibers and some degenerating fibers within the endplate region
• splitting fibers and fibers with increased central nuclei are common in endplate regions of older mutants
• motor endplates show strong staining for acid phosphatase and patchy acid phosphatase activity is seen throughout many fibers in the endplate region indicating increased lysosomal activity
• motor endplates show focal accumulation of calcium and ultrastructural changes, including enlargement and degeneration of the subsynaptic mitochondria and nuclei
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• mutants older than 4 months of age exhibit scattered angulated or atrophic fibers and some degenerating fibers within the endplate region
• degenerating myonucleus filled with autophagic debris and cytoplasmic contents
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• strength testing indicates skeletal muscle weakness; mice are able to grip the wire or dowel briefly but fatigue and drop off the apparatus before 60 seconds compared to controls that remain hanging or climb off
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nervous system
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• degeneration of neuromuscular synapses is seen by 4 months of age
• forelimb flexer muscle neuromuscular junctions show subsarcolemmal vacuoles of a range of sizes; some vacuoles appear empty and some contain electron-dense granular material and/or membranous debris
• forelimb neuromuscular junctions contain lysosomes filled with membranous debris and degenerating subsarcolemmal organelles
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• single stimuli to peripheral nerves evokes repetitive compound muscle action potentials (CMAP) in gastrocnemius muscle unlike in controls which show a single action potential; the repetitive firing of action potentials is caused by prolongation of the endplate potential beyond the muscle fiber refractory period
• these repetitive compound muscle action potentials in response to single peripheral nerve stimulus, however, are absent or diminished in intrinsic hindpaw muscles
• repetitive nerve stimulation at rates from 2 to 10 Hz over intrinsic muscles of the hindpaws elicit decremental compound muscle action potentials compared to controls that stay at a constant amplitude
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• abnormal neuromuscular transmission
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• patch-clamp analysis of acetylcholine-induced single channels in endplates shows channels with prolonged open durations; at a 50 mV holding potential, in the presence of 400 nM acetycholine, muscle fibers exhibit similar short duration events as controls, however, long duration events are more than 3-fold longer than corresponding events from controls
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• miniature endplate current (MEPC) decay phases are predominately biphasic (with one normal component and one slow component) and have significantly prolonged decay phases
• the quantally evoked MEPCs from diaphragm muscle have a 31% reduction in amplitude
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| congenital myasthenic syndrome 4A | DOID:0110678 |
OMIM:605809 |
J:193524 | |
