These transgenic mice express the L269F mutant form of the adult murine cholinergic receptor, nicotinic, epsilon polypeptide (Chrne) under control of the murine creatine kinase, muscle (Ckm) promoter. Chrne encodes the acetylcholine receptor (AChr) epsilon subunit AChRε, a subunit of the adult skeletal muscle AChR. Expressed in the neuromuscular junction, AChRs are ligand-gated ion channels that open in response to acetylcholine to elicit endplate potentials that evoke the muscle fiber action potentials and muscular contraction. A point mutation was introduced in CHRNE resulting in the εL269F mutation present in the affected members of two families with the slow-channel congenital myasthenic syndrome (SCCMS). SCCMS is a dominantly inherited disorder of neuromuscular transmission, characterized by fatigability and progressive weakness and atrophy of skeletal muscles. Hemizygous and homozygous εL269F mice are viable and fertile with a fine tremor and slow progressive weakness and fatigability. They exhibit impaired neuromuscular transmission with prolonged duration of neuromuscular endplate currents, reduced quantal content, and reduced endplate current amplitudes. They also display degeneration of the postsynaptic membrane, damage to subsynaptic nuclei and mitochondria, calcium overload of the postsynaptic region, and activation of calpain and caspase proteases in the postsynaptic region.
