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

J Clin Invest. 1999 Nov;104(10):1403-10. doi: 10.1172/JCI8179.


We describe a severe postsynaptic congenital myasthenic syndrome with marked endplate acetylcholine receptor (AChR) deficiency caused by 2 heteroallelic mutations in the beta subunit gene. One mutation causes skipping of exon 8, truncating the beta subunit before its M1 transmembrane domain, and abolishing surface expression of pentameric AChR. The other mutation, a 3-codon deletion (beta426delEQE) in the long cytoplasmic loop between the M3 and M4 domains, curtails but does not abolish expression. By coexpressing beta426delEQE with combinations of wild-type subunits in 293 HEK cells, we demonstrate that beta426delEQE 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 the beta subunit is crucial for interaction with the delta subunit. The findings imply that the mutated residues are positioned at the interface between beta and delta subunits and demonstrate contribution of this local region of the long cytoplasmic loop to AChR assembly.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alleles
  • Amino Acid Sequence
  • Animals
  • Child
  • Codon
  • Exons
  • Female
  • Humans
  • Macromolecular Substances
  • Male
  • Molecular Sequence Data
  • Motor Endplate / pathology
  • Motor Endplate / physiology
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology
  • Myasthenia Gravis, Neonatal / genetics*
  • Myasthenia Gravis, Neonatal / pathology
  • Myasthenia Gravis, Neonatal / physiopathology
  • Nuclear Family
  • Pedigree
  • Protein Structure, Secondary
  • Receptors, Cholinergic / chemistry
  • Receptors, Cholinergic / genetics*
  • Receptors, Cholinergic / metabolism
  • Reference Values
  • Sequence Alignment
  • Sequence Deletion*
  • Sequence Homology, Amino Acid


  • Codon
  • Macromolecular Substances
  • Receptors, Cholinergic
  • Acetylcholinesterase