Mutation causing congenital myasthenia reveals acetylcholine receptor beta/delta subunit interaction essential for assembly

We describe a severe postsynaptic congenital myasthenic syndrome with marke d endplate acetylcholine receptor (AChR) deficiency caused by 2 heteroallel ic mutations in the beta subunit gene. One mutation causes skipping of exon 8, truncating the beta subunit before its M1 transmembrane domain, and abo lishing surface expression of pentameric AChR. The other mutation, a 3-codo n deletion (beta 426delEQE) in the long cytoplasmic loop between the M3 and M4 domains, curtails but does not abolish expression. By coexpressing beta 426delEQE with combinations of wild-type subunits in 293 HEK cells, we dem onstrate that beta 426delEQE impairs AChR assembly by disrupting a specific interaction between beta and delta subunits. Studies with related deletion and missense mutants indicate that secondary structure in this region of t he beta subunit is crucial for interaction with the delta subunit. The find ings imply that the mutated residues are positioned at the interface betwee n beta and delta subunits and demonstrate contribution of this local region of the long cytoplasmic loop to AChR assembly.