Genetic and immunological analyses of patients with increased serum butyrylcholinesterase activity and its C5 variant form

Abstract

Recent evidence has denied genetic abnormality as a mechanism of the C5 variant of butyrylcholinesterase (BChE) and proposed the binding of an unknown protein with the C4 component. The present study aimed to evaluate whether the coding sequences and non-translated sequences of the BChE gene at exons 1 to 4, 3q are structurally different in subjects having elevated BChE with and without the C5 variant phenotype. We also attempted to identify the unknown protein associated with the C5 variant and measured the BChE-specific activity in the C5 variant with an enzyme-linked immunosorbent assay (ELISA) using anti-BChE monoclonal antibody. We investigated five subjects, four of whom had elevated plasma BChE (three C5-positive [C5(+)] and one C5-negative [C5(-)]) and one control with a normal plasma BChE level. Direct DNA sequencing of the BChE gene revealed no relevant genetic mutations and no abnormal migrations in the genes of all five subjects. Precipitation of the patients' sera with anti-human immunoglobulin A (IgA), -IgG, -IgM, anti-human albumin antibodies had no effect on the BChE activity. The measured BChE activity in C5(+) was 30 to 54% higher than the activity calculated from BChE protein content. The present results suggest that the C5(+) phenotype is not associated with any genetic abnormality in the CHE1 locus, and BChE-specific activity is enhanced in the C5(+) variant. However, the exact nature of the unknown protein related to the C5(+) phenotype remains unclear.

Association between RAPH1 Gene Haplotypes and CHE2 Locus Phenotypes

“…Considering that the work of Akizuki et al. () suggested that there is no relationship between increased BChE activity which occurs in CHE2 C5+ and variants of the BCHE gene, since no association between BCHE gene variants and CHE2 C5+ phenotype was observed, we can suppose that the responsible for increased activity in intense CHE2 C5+ individuals would be the Lpd.…”

Butyrylcholinesterase: Association with the Metabolic Syndrome and Identification of 2 Gene Loci Affecting Activity

“…A search through this region with current techniques would be time-consuming and expensive and not justified until the linkage result in this region has been replicated. One possibility that should be considered is that this region of chromosome 5 contains a gene for a protein that binds to cholinesterase and increases its activity (24 ); efforts to identify the nature of this protein by conventional biochemical means have been unsuccessful to date. Another possibility is that genes in this region affect the risk of insulin resistance and metabolic syndrome and that the linkage for cholinesterase activity is a consequence of this.…”

“…This occurs with a frequency of 8% to 10% among Europeans (22 ), and is ascribed to the effects of another gene, cholinesterase (serum), 2 (CHE2), whose location is uncertain (23 ). A recent report (24 ) has shown that the increased activity is not attributable to increased cholinesterase protein concentration, but rather to increased specific activity.…”

Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors

“…92 , 93 These variants have the wild-type BCHE nucleotide sequence in their exons and promoter region. 93 Heritable quantitative trait loci have been identified in intron 2 and the 3′-UTR of the BCHE gene and on chromosome 5q, 6 but it is unknown whether mutations at these loci increase or decrease BChE activity levels. Additional loci that affect BChE activity have been identified by the genome-wide association scan method.…”