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Lookup NU author(s): Emeritus Professor Clarke Slater
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Acetylcholine receptor (AChR) deficiency is the most common of the congenital myasthenic syndromes (CMS). Typically, the number of AChRs, measured by α-bungarotoxin binding, is reduced to 10-30% of normal levels, the miniature end-plate potentials are correspondingly reduced, and there are morphological changes at the motor end-plates. The majority of these syndromes are due to either missense or frameshift mutations within the gene encoding the adult-specific ε-subunit. These are often null mutations, but some mutant ε-subunits can be incorporated, at low levels, into functional AChRs in transfected cell lines. It is not clear, therefore, whether upregulation of the mutant ε-subunit mRNA could generate sufficient AChR to support neuromuscular transmission, albeit at a reduced level. Conversely, it might be that the mutant ε-subunit transcripts are subject to mRNA surveillance and 'nonsense-mediated' loss, leading to reduced ε-subunit mRNA expression. In either case, it is thought that neuromuscular transmission may be provided partly or entirely by incorporation of the foetal-specific γ-subunit into end-plate AChR. γ-Subunit mRNA is expressed at low levels in normal human muscle, but might be upregulated in CMS. The study of mRNA levels for AChR subunits should improve our understanding of genotype-phenotype relationships in CMS. Here we have defined homozygous ε-subunit mutations in four unrelated families with AChR deficiency and studied the steady-state levels of mRNA for AChR subunits at the motor end-plates by in situ hybridization. Although we demonstrated that each mutation would lead to almost complete absence of surface adult AChR expression, we detected similar robust expression of α- and ε-subunit mRNAs at end-plates of patient and control muscles, suggesting that mRNA transcripts for the ε-subunit are neither upregulated nor degraded preferentially. Interestingly, we were unable to detect any increase in γ-subunit mRNA expression at CMS end-plates. Transgenic mice lacking the ε-subunit die 2-3 months after birth, suggesting that α2βδ2pentamers cannot sustain neuromuscular transmission. Therefore, we tentatively conclude that the persistent low level expression of the γ-subunit, which is present in normal human muscles as well as in AChR deficiency syndromes, is sufficient to enable patients with ε-subunit null alleles to survive.
Author(s): Croxen R, Young C, Slater C, Haslam S, Brydson M, Vincent A, Beeson D
Publication type: Article
Publication status: Published
Journal: Brain
Year: 2001
Volume: 124
Issue: 7
Pages: 1362-1372
Print publication date: 01/01/2001
ISSN (print): 0006-8950
ISSN (electronic): 1460-2156
Publisher: Oxford University Press
URL: http://dx.doi.org/10.1093/brain/124.7.1362
DOI: 10.1093/brain/124.7.1362
PubMed id: 11408331
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