title: Structural heterogeneity of Caucasian N-acetyltransferase at the NAT1 gene locus.
abstract: The human N-acetylation polymorphism is a genetic trait phenotypically reflected by differences in N-acetyltransferase (NAT) activity with therapeutic agents (rapid and slow acetylation), but a genetic invariability in N-acetylation of some arylamine drugs is also known. There are two highly similar human NAT genes: NAT1 is thought to encode a genetically invariant protein, whereas NAT2 has conclusively been shown to represent a polymorphic locus. This study demonstrates the presence of discrete NAT1 structural variants among Caucasians. These were detected by direct sequencing of 1.6-kilobase NAT1 fragments generated by the polymerase chain reaction with liver and leukocyte DNA from 13 subjects of established acetylator phenotype and NAT2 genotype. A prominent alteration in one of the variants was obliteration of the consensus polyadenylation signal (AATAAA-->AAAAAA). Several mutations were discernible in all regions of the second variant allele, including silent (codon 153) and nonsilent (Ser-214-->Ala) substitutions in the coding region and deletion of nine bases from an AT-rich segment in the 3' untranslated region. One-half of the unrelated subjects were either homozygous or heterozygous for the mutant NAT1 alleles, both of which obeyed a Mendelian inheritance pattern. These novel results unambiguously show that human NAT1, like NAT2, is a polymorphic locus.
authors.affiliation: Department of Pharmacology, Medical School, University of Michigan, Ann Arbor 48109-0626.
authors.forename: K P
authors.initials: KP
authors.lastname: Vatsis
authors.forename: W W
authors.initials: WW
authors.lastname: Weber
mesh_terms: D000107:Acetylation; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D001483:Base Sequence; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007962:Leukocytes / Q000737:chemistry; D008099:Liver / Q000737:chemistry; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D044465:White People / Q000235:genetics*
chemical_list: D004247:DNA; D001191:Arylamine N-Acetyltransferase