CONGENITAL MYASTHENIC SYNDROME CAUSED BY PROLONGED ACETYLCHOLINE-RECEPTOR CHANNEL OPENINGS DUE TO A MUTATION IN THE M2 DOMAIN OF THE EPSILON-SUBUNIT

In a congenital myasthenic syndrome with a severe endplate myopathy, p atch-clamp studies revealed markedly prolonged acetylcholine receptor (AChR) channel openings. Molecular genetic analysis of AChR subunit ge nes demonstrated a heterozygous adenosine-to-cytosine transversion at nucleotide 790 in exon 8 of the epsilon-subunit gene, predicting subst itution of proline for threonine at codon 264 and no other mutations i n the entire coding sequences of genes encoding the (alpha, beta, delt a, and epsilon subunits. Genetically engineered mutant AChR expressed in a human embryonic kidney fibroblast cell line also exhibited marked ly prolonged openings in the presence of agonist and even opened in it s absence. The Thr-264 --> Pro mutation in the epsilon subunit involve s a highly conserved residue in the M2 domain lining the channel pore and is likely to disrupt the putative M2 alpha-helix. Our findings ind icate that a single mutation at a critical site can greatly alter AChR channel kinetics, leading to a congenital myasthenic syndrome. This o bservation raises the possibility that mutations involving subunits of other ligand-gated channels may also exist and be the basis of variou s other neurologic or psychiatric disorders.