Vesicular acetylcholine transporter defect underlies devastating congenital myasthenia syndrome

Neurology. 2017 Mar 14;88(11):1021-1028. doi: 10.1212/WNL.0000000000003720. Epub 2017 Feb 10.


Objective: To identify the genetic basis of a recessive congenital neurologic syndrome characterized by severe hypotonia, arthrogryposis, and respiratory failure.

Methods: Identification of the responsible gene by exome sequencing and assessment of the effect of the mutation on protein stability in transfected rat neuronal-like PC12A123.7 cells.

Results: Two brothers from a nonconsanguineous Yemeni Jewish family manifested at birth with severe hypotonia and arthrogryposis. The older brother died of respiratory failure at 5 days of age. The proband, now 4.5 years old, has been mechanically ventilated since birth with virtually no milestones achievement. Whole exome sequencing revealed homozygosity of SLC18A3 c.1078G>C, p.Gly360Arg in the affected brothers but not in other family members. SLC18A3 p.Gly360Arg is not reported in world populations but is present at a carrier frequency of 1:30 in healthy Yemeni Jews. SLC18A3 encodes the vesicular acetylcholine transporter (VAChT), which loads newly synthesized acetylcholine from the neuronal cytoplasm into synaptic vesicles. Mice that are VAChT-null have been shown to die at birth of respiratory failure. In human VAChT, residue 360 is located in a conserved region and substitution of arginine for glycine is predicted to disrupt proper protein folding and membrane embedding. Stable transfection of wild-type and mutant human VAChT into neuronal-like PC12A123.7 cells revealed similar mRNA levels, but undetectable levels of the mutant protein, suggesting post-translational degradation of mutant VAChT.

Conclusion: Loss of function of VAChT underlies severe arthrogryposis and respiratory failure. While most congenital myasthenic syndromes are caused by defects in postsynaptic proteins, VAChT deficiency is a presynaptic myasthenic syndrome.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Animals
  • Arginine / genetics
  • Family Health
  • Glycine / genetics
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation / genetics
  • Myasthenic Syndromes, Congenital / complications
  • Myasthenic Syndromes, Congenital / genetics*
  • Myasthenic Syndromes, Congenital / metabolism*
  • PC12 Cells
  • Protein Processing, Post-Translational / genetics
  • RNA, Messenger
  • Rats
  • Transfection
  • Vesicular Acetylcholine Transport Proteins / genetics
  • Vesicular Acetylcholine Transport Proteins / metabolism*


  • RNA, Messenger
  • Vesicular Acetylcholine Transport Proteins
  • Arginine
  • Glycine