Phenotypes Associated with This Genotype

Genotype
MGI:5478770

• Allelic Composition: Tg(Ckm-Chrne*L269F)5Cgz/?
• Genetic Background: involves: FVB/NJ

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

behavior/neurological

decreased locomotor activity ( J:193524 )

• by around 5 months of age, mutants show less spontaneous exploratory activity

homeostasis/metabolism

increased physiological sensitivity to xenobiotic ( J:193524 )

• mutants are more susceptible to fatal complications during pentobarbital anesthesia than controls

respiratory system

increased pulmonary respiratory rate ( J:193524 )

• mutants exhibit a faster respiratory rate by 6-8 weeks of age

muscle

abnormal skeletal muscle fiber morphology ( J:193524 )

• 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

skeletal muscle fiber degeneration ( J:193524 )

• 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

muscle weakness ( J:193524 )

• 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

nervous system

abnormal neuromuscular synapse morphology ( J:193524 )

• 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

abnormal action potential ( J:193524 )

• 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

abnormal PNS synaptic transmission ( J:193524 )

• abnormal neuromuscular transmission

abnormal endplate potential ( J:193524 )

• 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

abnormal miniature endplate potential ( J:193524 )

• 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

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
congenital myasthenic syndrome 4A		DOID:0110678	OMIM:605809	J:193524