Lindqvist Malin, Haglund Sofie, Almer Sven, Peterson Curt, Taipalensu Jan, Hertervig Erik, Lyrenäs Ebbe, Söderkvist Peter
Department of Medicine and Care, Division of Clinical Pharmacology, Faculty of Health Sciences, Linköping University, SE-58185 Linköping, Sweden.
Pharmacogenetics. 2004 Apr;14(4):261-5. doi: 10.1097/00008571-200404000-00006.
The polymorphic enzyme thiopurine methyltransferase (TPMT) is involved in the methylation of thiopurines. On comparing the phenotype with the genotype in Swedish patients with inflammatory bowel disease and healthy individuals, we found two discordant cases with low TPMT enzyme activity (0.3 and 0.4 U/ml packed red blood cells (pRBC). Genotyping by pyrosequencing revealed that they carried the nucleotide substitutions 460G>A and 719A>G, giving two possible genotypes (TPMT1/3A or TPMT3B/3C). DNA sequencing of exon III to X was performed in the patients and their parents. We identified an A>G transition in the start codon (exon III, 1A>G, Met>Val, TPMT14) in one of the patients and her father (6.3 U/ml pRBC). The mother in this family carried the 460G>A and 719A>G nucleotide substitutions (TPMT1/3A; 5.0 U/ml pRBC). In the second family, sequencing revealed a G>A transition in the acceptor splice site in intron VII/exon VIII (IVS7 -1G>A, TPMT15) in the patient and his mother (6.9 U/ml pRBC). His father was genotyped as TPMT*1/*3A (6.0 U/ml pRBC). Hence, we report the identification of two novel sequence variants, present in highly conserved nucleotide positions of the human TPMT gene, resulting in a loss of enzyme activity.
多态性酶硫嘌呤甲基转移酶（TPMT）参与硫嘌呤的甲基化过程。在比较瑞典炎性肠病患者和健康个体的表型与基因型时，我们发现了两例TPMT酶活性较低（分别为0.3和0.4 U/ml 压积红细胞（pRBC））的不一致病例。焦磷酸测序基因分型显示，他们携带核苷酸替换460G>A和719A>G，产生两种可能的基因型（TPMT1/3A或TPMT3B/3C）。对这些患者及其父母进行了外显子III至X的DNA测序。我们在其中一名患者及其父亲（6.3 U/ml pRBC）中鉴定出起始密码子（外显子III，1A>G，Met>Val，TPMT14）中的A>G转换。该家庭中的母亲携带460G>A和719A>G核苷酸替换（TPMT1/3A；5.0 U/ml pRBC）。在第二个家庭中，测序显示患者及其母亲（6.9 U/ml pRBC）的内含子VII/外显子VIII的剪接受体位点（IVS7 -1G>A，TPMT15）存在G>A转换。他的父亲基因分型为TPMT*1/*3A（6.0 U/ml pRBC）。因此，我们报告鉴定出两种新的序列变异，它们存在于人类TPMT基因高度保守的核苷酸位置，导致酶活性丧失。
