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Human Molecular Genetics Advance Access published online on October 7, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh320
© 2004 by Oxford University Press
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Article

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

Judy Cossins 1, Richard Webster 1, Susan Maxwell 1, Georgina Burke 1, Angela Vincent 1, and David Beeson 1*

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

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


  Abstract

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 characterised by non-progressive fatigable muscle weakness present throughout life. By 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 MEPPs and EPPs, reduced motor endplate AChR number and altered endplate morphology. Our results illustrate how species differences in the control of ion-channel gene expression may effect 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.


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