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

Jarvik, Gail P.a,b; Jampsa, Rachela; Richter, Rebecca J.a; Carlson, Chris S.b; Rieder, Mark J.b; Nickerson, Deborah A.b; Furlong, Clement E.a,b

doi: 10.1097/01.fpc.0000054086.48725.90
Orginal article

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. PON1192 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 PON1192 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 ( PON1Trp194stop ). It was predicted that subjects who genotyped as PON1192QR but phenotyped as PON1192QQ or PON1192RR 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 PON1192R 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: PON1Pro90Leu associated with the PON1192Q allele and PON1Asp124missplice associated with the PON1192R allele.

aDepartments of Medicine, Division of Medical Genetics

bGenome Sciences, The University of Washington, Seattle, Washington, USA.

Sponsorship: This work was funded by the National Institutes of Health HL67406 and the Veteran Affairs Epidemiology Research and Information Centre Program (award CSP 701S; G.P.J), with additional funding from NIH P30ESO7033, PO1ES09601, EPA-R 826886-01-0, and NIH ES09883 and the Program for Genomic Applications (PGA) NIH-NHLBI U01 HL66682 and U01 HL6642.

Correspondence and requests for reprints to Gail Jarvik, University of Washington Medical Center, Division of Medical Genetics, Box 357720, Seattle, WA 98195-7720, USA.

Tel: +1 206 685 9069; fax: +1 206 616 7186; e-mail:

Received 6 February 2003; Accepted 14 March 2003

© 2003 Lippincott Williams & Wilkins, Inc.