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Xenobiotic_sensitivity Report for: Hypersensitivity to acetylcholinesterase inhibitors

Alternative name(s)|
Mutation|2 mutations: g.-17113T>A_human-ACHE, g.-17116delTGTT_human-ACHE
OMIM: |100740

(from OMIM) Hypersensitivity to acetylcholinesterase inhibitors (anti-AChEs) causes severe nervous system symptoms under low dose exposure. Shapira et al. (2000) found a 4-bp deletion located 17 kb upstream of the transcription start site of human-ACHE that abolished 1 of 2 adjacent HNF3 (see 602294) binding sites. The allele frequency was 0.012, with a strong linkage between the deletion and the biochemically neutral his322-to-asn polymorphism of human-ACHE (YT2- blood group antigen). 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 3 spontaneous abortions. Electromobility shift assays, transfection studies, and measurements of AChE levels in immortalized lymphocytes and peripheral blood demonstrated increased AChE expression from the mutant allele, probably caused by alleviation of competition between the 2 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. The authors concluded that promoter polymorphism(s) in the ACHE gene are dominant susceptibility factor(s) for adverse responses to exposure or to treatment with anti-AChEs.

    Title: A transcription-activating polymorphism in the ACHE promoter associated with acute sensitivity to anti-acetylcholinesterases
    Shapira M, Tur-Kaspa I, Bosgraaf L, Livni N, Grant AD, Grisaru D, Korner M, Ebstein RP, Soreq H
    Ref: Hum Mol Genet, 9:1273, 2000 : PubMed


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Mail to: Nicolas Lenfant, Thierry Hotelier, Yves Bourne, Pascale Marchot and Arnaud Chatonnet.
Please cite: Lenfant 2013 Nucleic.Acids.Res. or Marchot Chatonnet 2012 Prot.Pept Lett.
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