title: Vesicular acetylcholine transporter defect underlies devastating congenital myasthenia syndrome.
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 PC12A123.7cells.
  
  
  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 ofSLC18A3c.1078G>C, p.Gly360Arg in the affected brothers but not in other family members.SLC18A3p.Gly360Arg is not reported in world populations but is present at a carrier frequency of 1:30 in healthy Yemeni Jews.SLC18A3encodes 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 PC12A123.7cells revealed similar mRNA levels, but undetectable levels of the mutant protein, suggesting post-translational degradation of mutant VAChT.
  
  
  CONCLUSIONS
  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.
authors.affiliation: From the Neuropediatric Unit (A.A.) and Medical Genetics (R.S., P.R., A.W.-S., S.Z., E.L.-L.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., R.S., A.W.-S., E.L.-L.), Jerusalem, Israel; Department of Chemistry and Biochemistry (K.K., S.O., S.M.P.), University of California, Santa Barbara; Faculty of Medicine (T.M., Y.H., A.O.S.), Bar Ilan University, Safed, Israel; and Departments of Medicine and Genome Sciences (S.G., M.K.L., M.-C.K., T.W.), University of Washington, Seattle.
authors.forename: Adi
authors.initials: A
authors.lastname: Aran
authors.affiliation: From the Neuropediatric Unit (A.A.) and Medical Genetics (R.S., P.R., A.W.-S., S.Z., E.L.-L.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., R.S., A.W.-S., E.L.-L.), Jerusalem, Israel; Department of Chemistry and Biochemistry (K.K., S.O., S.M.P.), University of California, Santa Barbara; Faculty of Medicine (T.M., Y.H., A.O.S.), Bar Ilan University, Safed, Israel; and Departments of Medicine and Genome Sciences (S.G., M.K.L., M.-C.K., T.W.), University of Washington, Seattle.
authors.forename: Reeval
authors.initials: R
authors.lastname: Segel
authors.affiliation: From the Neuropediatric Unit (A.A.) and Medical Genetics (R.S., P.R., A.W.-S., S.Z., E.L.-L.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., R.S., A.W.-S., E.L.-L.), Jerusalem, Israel; Department of Chemistry and Biochemistry (K.K., S.O., S.M.P.), University of California, Santa Barbara; Faculty of Medicine (T.M., Y.H., A.O.S.), Bar Ilan University, Safed, Israel; and Departments of Medicine and Genome Sciences (S.G., M.K.L., M.-C.K., T.W.), University of Washington, Seattle.
authors.forename: Kota
authors.initials: K
authors.lastname: Kaneshige
authors.affiliation: From the Neuropediatric Unit (A.A.) and Medical Genetics (R.S., P.R., A.W.-S., S.Z., E.L.-L.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., R.S., A.W.-S., E.L.-L.), Jerusalem, Israel; Department of Chemistry and Biochemistry (K.K., S.O., S.M.P.), University of California, Santa Barbara; Faculty of Medicine (T.M., Y.H., A.O.S.), Bar Ilan University, Safed, Israel; and Departments of Medicine and Genome Sciences (S.G., M.K.L., M.-C.K., T.W.), University of Washington, Seattle.
authors.forename: Suleyman
authors.initials: S
authors.lastname: Gulsuner
authors.affiliation: From the Neuropediatric Unit (A.A.) and Medical Genetics (R.S., P.R., A.W.-S., S.Z., E.L.-L.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., R.S., A.W.-S., E.L.-L.), Jerusalem, Israel; Department of Chemistry and Biochemistry (K.K., S.O., S.M.P.), University of California, Santa Barbara; Faculty of Medicine (T.M., Y.H., A.O.S.), Bar Ilan University, Safed, Israel; and Departments of Medicine and Genome Sciences (S.G., M.K.L., M.-C.K., T.W.), University of Washington, Seattle.
authors.forename: Paul
authors.initials: P
authors.lastname: Renbaum
authors.affiliation: From the Neuropediatric Unit (A.A.) and Medical Genetics (R.S., P.R., A.W.-S., S.Z., E.L.-L.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., R.S., A.W.-S., E.L.-L.), Jerusalem, Israel; Department of Chemistry and Biochemistry (K.K., S.O., S.M.P.), University of California, Santa Barbara; Faculty of Medicine (T.M., Y.H., A.O.S.), Bar Ilan University, Safed, Israel; and Departments of Medicine and Genome Sciences (S.G., M.K.L., M.-C.K., T.W.), University of Washington, Seattle.
authors.forename: Scott
authors.initials: S
authors.lastname: Oliphant
authors.affiliation: From the Neuropediatric Unit (A.A.) and Medical Genetics (R.S., P.R., A.W.-S., S.Z., E.L.-L.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., R.S., A.W.-S., E.L.-L.), Jerusalem, Israel; Department of Chemistry and Biochemistry (K.K., S.O., S.M.P.), University of California, Santa Barbara; Faculty of Medicine (T.M., Y.H., A.O.S.), Bar Ilan University, Safed, Israel; and Departments of Medicine and Genome Sciences (S.G., M.K.L., M.-C.K., T.W.), University of Washington, Seattle.
authors.forename: Tomer
authors.initials: T
authors.lastname: Meirson
authors.affiliation: From the Neuropediatric Unit (A.A.) and Medical Genetics (R.S., P.R., A.W.-S., S.Z., E.L.-L.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., R.S., A.W.-S., E.L.-L.), Jerusalem, Israel; Department of Chemistry and Biochemistry (K.K., S.O., S.M.P.), University of California, Santa Barbara; Faculty of Medicine (T.M., Y.H., A.O.S.), Bar Ilan University, Safed, Israel; and Departments of Medicine and Genome Sciences (S.G., M.K.L., M.-C.K., T.W.), University of Washington, Seattle.
authors.forename: Ariella
authors.initials: A
authors.lastname: Weinberg-Shukron
authors.affiliation: From the Neuropediatric Unit (A.A.) and Medical Genetics (R.S., P.R., A.W.-S., S.Z., E.L.-L.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., R.S., A.W.-S., E.L.-L.), Jerusalem, Israel; Department of Chemistry and Biochemistry (K.K., S.O., S.M.P.), University of California, Santa Barbara; Faculty of Medicine (T.M., Y.H., A.O.S.), Bar Ilan University, Safed, Israel; and Departments of Medicine and Genome Sciences (S.G., M.K.L., M.-C.K., T.W.), University of Washington, Seattle.
authors.forename: Yair
authors.initials: Y
authors.lastname: Hershkovitz
authors.affiliation: From the Neuropediatric Unit (A.A.) and Medical Genetics (R.S., P.R., A.W.-S., S.Z., E.L.-L.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., R.S., A.W.-S., E.L.-L.), Jerusalem, Israel; Department of Chemistry and Biochemistry (K.K., S.O., S.M.P.), University of California, Santa Barbara; Faculty of Medicine (T.M., Y.H., A.O.S.), Bar Ilan University, Safed, Israel; and Departments of Medicine and Genome Sciences (S.G., M.K.L., M.-C.K., T.W.), University of Washington, Seattle.
authors.forename: Sharon
authors.initials: S
authors.lastname: Zeligson
authors.affiliation: From the Neuropediatric Unit (A.A.) and Medical Genetics (R.S., P.R., A.W.-S., S.Z., E.L.-L.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., R.S., A.W.-S., E.L.-L.), Jerusalem, Israel; Department of Chemistry and Biochemistry (K.K., S.O., S.M.P.), University of California, Santa Barbara; Faculty of Medicine (T.M., Y.H., A.O.S.), Bar Ilan University, Safed, Israel; and Departments of Medicine and Genome Sciences (S.G., M.K.L., M.-C.K., T.W.), University of Washington, Seattle.
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.affiliation: From the Neuropediatric Unit (A.A.) and Medical Genetics (R.S., P.R., A.W.-S., S.Z., E.L.-L.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., R.S., A.W.-S., E.L.-L.), Jerusalem, Israel; Department of Chemistry and Biochemistry (K.K., S.O., S.M.P.), University of California, Santa Barbara; Faculty of Medicine (T.M., Y.H., A.O.S.), Bar Ilan University, Safed, Israel; and Departments of Medicine and Genome Sciences (S.G., M.K.L., M.-C.K., T.W.), University of Washington, Seattle.
authors.forename: Abraham O
authors.initials: AO
authors.lastname: Samson
authors.affiliation: From the Neuropediatric Unit (A.A.) and Medical Genetics (R.S., P.R., A.W.-S., S.Z., E.L.-L.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., R.S., A.W.-S., E.L.-L.), Jerusalem, Israel; Department of Chemistry and Biochemistry (K.K., S.O., S.M.P.), University of California, Santa Barbara; Faculty of Medicine (T.M., Y.H., A.O.S.), Bar Ilan University, Safed, Israel; and Departments of Medicine and Genome Sciences (S.G., M.K.L., M.-C.K., T.W.), University of Washington, Seattle.
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Parsons
authors.affiliation: From the Neuropediatric Unit (A.A.) and Medical Genetics (R.S., P.R., A.W.-S., S.Z., E.L.-L.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., R.S., A.W.-S., E.L.-L.), Jerusalem, Israel; Department of Chemistry and Biochemistry (K.K., S.O., S.M.P.), University of California, Santa Barbara; Faculty of Medicine (T.M., Y.H., A.O.S.), Bar Ilan University, Safed, Israel; and Departments of Medicine and Genome Sciences (S.G., M.K.L., M.-C.K., T.W.), University of Washington, Seattle.
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.affiliation: From the Neuropediatric Unit (A.A.) and Medical Genetics (R.S., P.R., A.W.-S., S.Z., E.L.-L.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., R.S., A.W.-S., E.L.-L.), Jerusalem, Israel; Department of Chemistry and Biochemistry (K.K., S.O., S.M.P.), University of California, Santa Barbara; Faculty of Medicine (T.M., Y.H., A.O.S.), Bar Ilan University, Safed, Israel; and Departments of Medicine and Genome Sciences (S.G., M.K.L., M.-C.K., T.W.), University of Washington, Seattle. lahad@szmc.org.il.
authors.forename: Ephrat
authors.initials: E
authors.lastname: Levy-Lahad
authors.affiliation: From the Neuropediatric Unit (A.A.) and Medical Genetics (R.S., P.R., A.W.-S., S.Z., E.L.-L.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., R.S., A.W.-S., E.L.-L.), Jerusalem, Israel; Department of Chemistry and Biochemistry (K.K., S.O., S.M.P.), University of California, Santa Barbara; Faculty of Medicine (T.M., Y.H., A.O.S.), Bar Ilan University, Safed, Israel; and Departments of Medicine and Genome Sciences (S.G., M.K.L., M.-C.K., T.W.), University of Washington, Seattle.
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
mesh_terms: D000328:Adult; D000818:Animals; D001120:Arginine / Q000235:genetics; D005192:Family Health; D005998:Glycine / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D020294:Myasthenic Syndromes, Congenital / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D016716:PC12 Cells; D011499:Protein Processing, Post-Translational / Q000235:genetics; D012333:RNA, Messenger; D051381:Rats; D014162:Transfection; D050494:Vesicular Acetylcholine Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D050494:Vesicular Acetylcholine Transport Proteins; D001120:Arginine; D005998:Glycine