Engel_1996_Ann.Neurol_40_810

We describe a congenital myasthenic syndrome associated with severe end-plate (EP) acetylcholine receptor (AChR) deficiency not associated with an EP myopathy, and with evidence of immature AChR, containing the gamma instead of the epsilon subunit (gamma-AChR) at the EPs. Molecular genetic analysis of AChR-subunit genes revealed two mutations in the epsilon-subunit gene: insertion of a thymine after epsilon nucleotide 1101 (epsilon 11O1insT) that generates a nonsense codon directly, and insertion of a guanine after epsilon nucleotide 1293 (epsilon 1293insG) that generates three missense codons followed by a nonsense codon. Each mutation predicts truncation of the epsilon subunit at the level of the long cytoplasmic loop, between the third (M3) and fourth (M4) membrane spanning domains. The propositus' asymptomatic son carries epsilon 1293G, indicating that the two mutations are heteroallelic. Expression of AChR harboring either mutation in human embryonic kidney (HEK) fibroblasts was markedly reduced. Single-channel activity recorded from HEK cells expressing epsilon 11O1insT-AChR was infrequent but resembled activity of wild-type AChR channels in amplitude and open duration. No channel activity could be recorded from HEK cells expressing epsilon 1293insG-AChR. Expression of gamma-AChR at the EPs may serve as the means of phenotypic rescue from potentially fatal nonsense mutations in the epsilon-subunit gene.