A transcription-activating polymorphism in the ACHE promoter associated with acute sensitivity to anti-acetylcholinesterases

Michael Shapira, Ilan Tur-Kaspa, Leonard Bosgraaf, Nadav Livni, Alastair D. Grant, Dan Grisaru, Mira Korner, Richard P. Ebstein, Hermona Soreq

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


Hypersensitivity to acetylcholinesterase inhibitors (anti-AChEs) causes severe nervous system symptoms under low dose exposure. In search of direct genetic origin(s) for this sensitivity, we studied six regions in the extended 22 kb promoter of the ACHE gene in individuals who presented adverse responses to anti-AChEs and in randomly chosen controls. Two contiguous mutations, a T→A substitution, disrupting a putative glucocorticoid response element, and a 4-bp deletion, abolishing one of two adjacent HNF3 binding sites, were identified 17 kb upstream of the transcription start site. Allele frequencies for these mutations were 0.006 and 0.012, respectively, in 333 individuals of various ethnic origins, with a strong linkage between the deletion and the biochemically neutral H322N mutation in the coding region of ACHE. Heterozygous carriers of the deletion included a proband who presented with acute hypersensitivity to the anti-AChE pyridostigmine and another with unexplained excessive vomiting during a fourth pregnancy following three spontaneous abortions. Electromobility shift assays, transfection studies and measurements of AChE levels in immortalized lymphocytes as well as in peripheral blood from both carriers and non-carriers, revealed functional relevance for this mutation both in vitro and in vivo and showed it to increase AChE expression, probably by alleviating competition between the two hepatocyte nuclear factor 3 binding sites. Moreover, AChE-overexpressing transgenic mice, unlike normal FVB/N mice, displayed anti-AChE hypersensitivity and failed to transcriptionally induce AChE production following exposure to anti-AChEs. Our findings point to promoter polymorphism(s) in the ACHE gene as the dominant susceptibility factor(s) for adverse responses to exposure or to treatment with antiAChEs.

Original languageEnglish
Pages (from-to)1273-1281
Number of pages9
JournalHuman Molecular Genetics
Issue number9
StatePublished - 22 May 2000

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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