Novel paraoxonase (PON1) nonsense and missense mutations predicted by functional genomic assay of PON1 status

Abstract

Paraoxonase (PON1) has been termed an environmental response enzyme for its function in the detoxification of organophosphate pesticides, nerve agents and pharmaceuticals such as glucocorticoids and statins, as well as its cardioprotective role in breaking down oxidized LDL. PON1(192) genotype can be predicted with high accuracy from an examination of the two-dimensional plot of paraoxon and diazoxon hydrolysis rates [ 1]. Individuals for whom this functional genomic assay failed to predict PON1(192) genotype, or who had a low PON activity relative to others with the same genotype, were predicted to have genetic alterations that explained the inconsistency. Sequencing of the PON1 region of 23 Caucasian individuals detected a nonsense mutation changing amino acid 194 from a Trp to a stop codon (PON1(Trp194stop)). It was predicted that subjects who genotyped as PON1(192QR) but phenotyped as PON1(192QQ) or PON1(192RR) might carry the protein truncation mutation for which the defective product failed to be detected by the phenotyping assay. Screening of the five discordant subjects resulted in the detection of a single Caucasian carrying the stop codon, and determined its phasing on the PON1(192R) allele. Sequencing confirmed the change and revealed an additional subject with a likely deletion of the 5' end of the PON1 gene. Additional sequencing of 25 subjects with low PON1 activities identified two additional previously undescribed PON1 mutations, which may affect PON1 function: PON1(Pro90Leu) associated with the PON1(192Q) allele and PON1(Asp124missplice) associated with the PON1(192R) allele.

Paraoxonase status and plasma butyrylcholinesterase activity in chlorpyrifos manufacturing workers

“…Diazoxonase activity versus paraoxonase (PONase) activity (upper plot) and chlorpyrifosoxonase (CPOase) activity versus PONase activity (lower plot) for chlorpyrifos subjects (filled symbols) and referent subjects (open symbols). Inferred genotypes were derived from the clustering observed in the diazoxonase versus PONase plot (Furlong et al, 2000b;Jarvik et al, 2003).…”

The correlation of paraoxonase (PON1) activity with lipid and lipoprotein levels differs with vascular disease status

“…Arylase was measured in triplicate. The plot of POase versus DZOase accurately predicts PON1 192 genotype in both cases and controls; this plot was used to fill in three missing genotypes (39).…”

HDL-Associated Paraoxonase 1 Gene Polymorphisms as a Genetic Markers for Wide Spread Diseases

“…Human clinical studies suggest that PON1 phenotype, i.e., paraoxonase activity is a much stronger predictor of cardiovascular disease status than PON1 genetic polymorphisms [51][52][53][54][55] a finding that has been confirmed in other studies [52,55]. Bhattacharyya and colleagues demonstrated that both the pon1 Q192R polymorphism and serum PON1 activity are associated with prevalent coronary artery disease and incident adverse cardiovascular events [56].…”