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

Hypersensitivity to acetylcholinesterase inhibitors (anti-AChEs) causes sev ere nervous system symptoms under low dose exposure. In search of direct ge netic origin(s) for this sensitivity, we studied six regions in the extende d 22 kb promoter of the ACHE gene in individuals who presented adverse resp onses to anti-AChEs and in randomly chosen controls. Two contiguous mutatio ns, a T-->A substitution, disrupting a putative glucocorticoid response ele ment, and a 4-bp deletion, abolishing one of two adjacent HNF3 binding site s, were identified 17 kb upstream of the transcription start site. Allele f requencies for these mutations were 0.006 and 0.012, respectively, in 333 i ndividuals of various ethnic origins, with a strong linkage between the del etion and the biochemically neutral H322N mutation in the coding region of ACHE. Heterozygous carriers of the deletion included a proband who presente d with acute hypersensitivity to the anti-AChE pyridostigmine and another w ith unexplained excessive vomiting during a fourth pregnancy following thre e 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 r elevance for this mutation both in vitro and in vivo and showed it to incre ase AChE expression, probably by alleviating competition between the two he patocyte nuclear factor 3 binding sites. Moreover, AChE-overexpressing tran sgenic 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 g ene as the dominant susceptibility factor(s) for adverse responses to expos ure or to treatment with anti-AChEs.