Vesicular acetylcholine transporter defect underlies devastating congenital myasthenia syndrome. (14th March 2017)

• Record Type: Journal Article
• Authors: Aran, Adi; Segel, Reeval; Kaneshige, Kota; Gulsuner, Suleyman; Renbaum, Paul; Oliphant, Scott; Meirson, Tomer; Weinberg-Shukron, Ariella; Hershkovitz, Yair; Zeligson, Sharon; Lee, Ming K.; Samson, Abraham O.; Parsons, Stanley M.; King, Mary-Claire; Levy-Lahad, Ephrat; Walsh, Tom
• Is Part Of: Neurology. Volume 88:Number 11(2017)
• Publication Date: 2017-03-14
• Subjects: Neurology -- Periodicals; Neurology -- Periodicals; Neurologie -- Périodiques; 616.8
• DOI: 10.1212/WNL.0000000000003720
• Languages: English
• ISSNs: 0028-3878

Abstract

Abstract : 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 PC12 A123.7 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 PC12 A123.7 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.