International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


ORAL PRESENTATION

TUESDAY OCTOBER 19

9.45am – 10.00am

SIGNIFICANCE OF GENETIC VARIABILITY IN THE HUMAN PON1 GENE EXPLORED IN A MOUSE MODEL

Furlong CE1, Cole TB1, Richter RJ1, Li WF1, Carlson C1, Nickerson D1, Jarvik GP1, Lusis AJ2, Tward A2, Shih D2, Costa LG1

1 University of Washington, Seattle, United States, 2 UCLA, Los Angeles, United States

Paraoxonase (PON1), an HDL-associated enzyme, exhibits broad substrate specificity.  While its main physiological role appears to be the metabolism of oxidized lipids and prevention of vascular disease, it also metabolizes organophosphates and several drugs.  More than 160 PON1 SNPs have been identified.  The Q192R protein polymorphism affects catalytic efficiency of hydrolysis of some compounds. The 5’ regulatory region SNP at C-108T is in a SP1 binding site and affects plasma levels of PON1.  The term “PON1 status” reflects both an individual’s PON1 plasma level and Q192R genotype. A “humanized” mouse PON1 model has provided valuable insights into the significance of variability in the human PON1 gene. PON1-/- mice show dramatically increased sensitivity to diazoxon (DZO) and chlorpyrifos oxon (CPO), but not to paraoxon.  Thus, PON1 activity in vitro does not necessarily indicate physiological significance. Differences in sensitivity are explained by the catalytic efficiency of each PON1192 alloform. Injection of purified human PON1Q192 or PON1R192 restored resistance to DZO, but only PON1R192 provided significant resistance to CPO.  These observations are consistent with the sensitivities of the “humanized” PON1Q192R transgenic mice.  Mice expressing hPON1Q192 were nearly as sensitive as the null mice to CPO exposure, whereas the hPON1R192 mice exhibited significant resistance.  These observations are significant in that PON1Q192 homozygotes comprise about 50% of the individuals in many populations.  Supported by ES09601/EPA-R826886, ES09883, ES04696, ES07033, ES11387, T32 AG00057.

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