End-Plate Acetylcholine Receptor Deficiency Due to Nonsense Mutations in the Epsilon Subunit

ENGEL, A.G.; OHNO, K.; BOUZAT, C.; SINE, S.M.; GRIGGS, R.C.

ANNALS OF NEUROLOGY

WILEY-LISS, DIV JOHN WILEY & SONS INC

Año: 1996 vol. 40 p. 810 - 817

0364-5134

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 γ instead of the epsiv; subunit (γ-AChR) at the EPs. Molecular genetic analysis of AChR-subunit genes revealed two mutations in the ε-subunit gene: insertion of a thymine after ε nucleotide 1101 (ε1101insT) that generates a nonsense condon directly, and insertionof a guanine after ε nucleotide 1293 (ε1293insG) that generates three missense codons followed by a nonsense codon. Each mutation predits truncation of the ε subunit at the level of the long cytoplasmic loop, between the third (M3) and fourth (M4) membrane spanning domains. The propositus´ asymptomatic son carries ε1293G, indicating that the two mutations are heteroallelic. Expression of AChR harboring either mutation in human embryonic kidney (HEK) fibroblasts was markedly reduced. Single-channel activit recorded from HEK cells cells expressin ε 1101insT-AChR was infrequent but resembled activty of wild-tpe AChR channels in amplitude and open duration. No channel activity could be recorded from HEK cells expressing ε 1293insG-AChR. Expression of γAChR at the EPs may serve as the means of phenotypic rescue from potentially fatal nonsense mutations in the ε-subunit gene.