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Human Molecular Genetics Advance Access originally published online on October 7, 2004
Human Molecular Genetics 2004 13(23):2947-2957; doi:10.1093/hmg/ddh320
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Human Molecular Genetics, Vol. 13, No. 23 © Oxford University Press 2004; all rights reserved

A mouse model of AChR deficiency syndrome with a phenotype reflecting the human condition

Judy Cossins, Richard Webster, Susan Maxwell, Georgina Burke, Angela Vincent and David Beeson*

Neurosciences Group, Weatherall Institute of Molecular Medicine, The John Radcliffe, Oxford OX3 9DS, UK

Received July 30, 2004; Accepted September 26, 2004

The two subtypes of mammalian muscle nicotinic acetylcholine receptors (AChR) are generated by the substitution of the {varepsilon} (adult) subunit for the {gamma} (fetal) subunit within the AChR pentamer. Null mutations of the adult AChR {varepsilon}-subunit gene are the most common cause of the AChR deficiency syndrome. This is a disorder of neuromuscular transmission characterized by non-progressive fatigable muscle weakness present throughout life. In contrast with the human disorder, mice with AChR {varepsilon}-subunit null mutations die between 10 and 14 weeks of age. We generated transgenic mice that constitutively express the human AChR {gamma}-subunit in an AChR {varepsilon}-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 {gamma}-subunit could be a beneficial therapeutic strategy.

* To whom correspondence should be addressed. Email: dbeeson{at}hammer.imm.ox.ac.uk


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