Ddh320 2947..2957
نویسندگان
چکیده
The two subtypes of mammalian muscle nicotinic acetylcholine receptors (AChR) are generated by the substitution of the 1 (adult) subunit for the g (fetal) subunit within the AChR pentamer. Null mutations of the adultAChR 1-subunit gene are themost commoncauseof theAChRdeficiencysyndrome. This is adisorder of neuromuscular transmission characterizedbynon-progressive fatigablemuscleweaknesspresent throughout life. In contrast with the human disorder, mice with AChR 1-subunit null mutations die between 10 and 14 weeks of age. We generated transgenic mice that constitutively express the human AChR g-subunit in an AChR 1-subunit ‘knock-out’ background. These mice, in which neuromuscular transmission is mediated by fetal AChR, live well into adult life but show striking similarities to human AChR deficiency syndrome. They display fatigable muscle weakness, reduced miniature endplate potentials and endplate potentials, reduced motor endplate AChR number and altered endplate morphology. Our results illustrate how species differences in the control of ion-channel gene expression may affect disease phenotype, demonstrate that expression of adult AChR subtype is not essential for long-term survival, and suggest that in patients with AChR deficiency syndrome, up-regulation of the g-subunit could be a beneficial therapeutic strategy.
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