GENOTYPING HUMAN ARYLAMINE N-ACETYLTRANSFERASE TYPE-1 (NAT1) - THE IDENTIFICATION OF 2 NOVEL ALLELIC VARIANTS

Human arylamine N-acetyltransferase (NAT) is known to exist as two iso enzymes, NAT1 and NAT2, with different though overlapping substrate sp ecificities. NAT1 and NAT2 are polymorphic at both genetic and phenoty pic levels with four distinct alleles described in Caucasians for NAT1 . Though clear genotype/phenotype associations exist for NAT2, the sam e remains unclear for NAT1. Whole blood taken from 32 individuals were NAT1 genotyped and compared to previously obtained NAT1 activities us ing p-aminobenzoic acid as a substrate [1]. The NAT1 alleles of one in dividual, who had low NAT1 activity, were sequenced and compared to th e wild type allele NAT14. A novel, non conservative, substitution was present in both alleles at nucleotide position 560 and results in the exchange oi an arginine for a glutamine at amino acid position 187. A glutamine is found in NAT2 at amino acid position 187 and has been im plicated in substrate binding. This report describes a simple and effe ctive genotyping method which detects the four previously reported NAT 1 polymorphisms, and the described novel low acetylating polymorphism by either NAT1 allele specific-PCR amplification or restriction fragme nt length polymorphism analysis of PCR amplified products. We suggest that NAT1 genotype/phenotype correlations will become more clear as fu rther allelic variants are determined. (C) 1998 Elsevier Science Inc.