MUTATIONS AND IMPAIRED EXPRESSION IN THE ACHE AND BCHE GENES - NEUROLOGICAL IMPLICATIONS

The acetylcholine hydrolysing cholinesterases control the termination of cholinergic signalling in multiple tissues and are targets for a va riety of drugs, natural and man-made poisons and common insecticides. Molecular cloning and gene mapping studies revealed the primary struct ure of human acetyl- and butyrylcholinesterase and localized the corre sponding ACHE and BCHE genes to the chromosomal positions 3q26-ter and 7q22, respectively. Several different point mutations in the coding r egion of BCHE were found to be particularly abundant in the Israeli po pulation. Analytical expression studies in microinjected Xenopus oocyt es have demonstrated that the biochemical properties of cholinesterase s may be modified by rationalized site-directed mutagenesis and in chi meric ACHE/BCHE constructs. These properties are differently altered i n the various allelic BCHE variants, conferring resistance to several anti-cholinesterases, which may explain the evolutionary emergence of these multiple alleles. At the clinical level, abnormal expression of both ACHE and BCHE and the in vivo amplification of the ACHE and BCHE genes has been variously associated with abnormal megakaryocytopoiesis , leukemias and brain and ovarian tumors. Moreover, antisense oligonuc leotides blocking the expression of these genes were shown to interfer e with hemocytopoiesis in culture, implicating these genes in choliner gic influence on cell growth and proliferation.