STRUCTURAL HETEROGENEITY OF CAUCASIAN N-ACETYLTRANSFERASE AT THE NAT1 GENE LOCUS
STRUCTURAL HETEROGENEITY OF CAUCASIAN N-ACETYLTRANSFERASE AT THE NAT1 GENE LOCUS
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DOI：
10.1006/abbi.1993.1116
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发表时间：
1993-02-15
影响因子：
3.9
通讯作者：
WEBER, WW
中科院分区：
文献类型：
--
作者：
VATSIS, KP;WEBER, WW
人类N-乙酰化多态性是一种遗传性状，其表型反映为治疗药物的N-乙酰转移酶（NAT）活性差异（快速和缓慢乙酰化），但也已知某些芳胺药物的N-乙酰化具有遗传不变性。有两个高度相似的人类NAT基因：NAT 1被认为编码一种遗传不变的蛋白质，而NAT 2已被证明代表一个多态性位点。这项研究证明了高加索人中存在离散的NAT 1结构变异。通过对13例乙酰化表型和NAT 2基因型受试者的肝脏和白细胞DNA进行聚合酶链反应产生的1.6-乙酰化酶NAT 1片段进行直接测序，检测到这些基因。其中一个变异体的显著改变是共有多聚腺苷酸化信号消失（AATAAA→AAAAAA）。在第二个变异等位基因的所有区域都可以识别出几个突变，包括编码区的沉默（密码子153）和非沉默（Ser-214→Ala）取代以及3′非翻译区富含AT片段的9个碱基缺失。一半的无关受试者是纯合子或杂合子的突变体NAT 1等位基因，这两个服从孟德尔遗传模式。这些新的结果明确地表明，人类NAT 1，像NAT 2，是一个多态位点。
The human N-acetylation polymorphism is a genetic trait phenotypically reflected by differences inN-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:NAT1is thought to encode a genetically invariant protein, whereasNAT2has conclusively been shown to represent a polymorphic locus. This study demonstrates the presence of discreteNAT1structural variants among Caucasians. These were detected by direct sequencing of 1.6-kilobaseNAT1fragments generated by the polymerase chain reaction with liver and leukocyte DNA from 13 subjects of established acetylator phenotype andNAT2genotype. 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 mutantNAT1alleles, both of which obeyed a Mendelian inheritance pattern. These novel results unambiguously show that humanNAT1, likeNAT2, is a polymorphic locus.