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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 alpha-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 epsilon-subunit. These are often null mutations, but some mutant epsilon-subunits can be incorporated, at low levels, into functional AChRs in transfected cell lines. It is not clear, therefore, whether upregulation of the mutant epsilon-subunit mRNA could generate sufficient AChR to support neuromuscular transmission, albeit at a reduced level. Conversely, it might be that the mutant epsilon-subunit transcripts are subject to mRNA surveillance and 'nonsense-mediated' loss, leading to reduced epsilon-subunit mRNA expression. In either case, it is thought that neuromuscular transmission may be provided partly or entirely by incorporation of the foetal-specific gamma-subunit into end-plate AChR. gamma-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 epsilon-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 alpha- and epsilon-subunit mRNAs at end-plates of patient and control muscles, suggesting that mRNA transcripts for the epsilon-subunit are neither upregulated nor degraded preferentially. Interestingly, we were unable to detect any increase in gamma-subunit mRNA expression at CMS end-plates. Transgenic mice lacking the epsilon-subunit die 2-3 months after birth, suggesting that alpha(2)betadelta(2) pentamers cannot sustain neuromuscular transmission. Therefore, we tentatively conclude that the persistent low level expression of the gamma-subunit, which is present in normal human muscles as well as in AChR deficiency syndromes, is sufficient to enable patients with epsilon-subunit null alleles to survive.


Journal article



Publication Date





1362 - 1372


Adult, Amino Acid Sequence, Base Sequence, Biopsy, Bungarotoxins, Cell Line, Child, DNA Mutational Analysis, Female, Gene Expression, Homozygote, Humans, In Situ Hybridization, Kidney, Male, Molecular Sequence Data, Motor Endplate, Muscle, Skeletal, Mutation, Myasthenic Syndromes, Congenital, Pedigree, Polymorphism, Single-Stranded Conformational, Protein Subunits, RNA, Messenger, Receptors, Cholinergic, Transfection