Wei X, Elizondo G, Sapone A, McLeod H L, Raunio H, Fernandez-Salguero P, Gonzalez F J
National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Genomics. 1998 Aug 1;51(3):391-400. doi: 10.1006/geno.1998.5379.
Dihydropyrimidine dehydrogenase (DPD) catabolizes endogenous pyrimidines and pyrimidine-based antimetabolite drugs. A deficiency in human DPD is associated with congenital thymine-uraciluria in pediatric patients and severe 5-fluorouracil toxicity in cancer patients. The dihydropyrimidine dehydrogenase gene (DPYD) was isolated, and its physical map and exon-intron organization were determined by analysis of P1, PAC, BAC, and YAC clones. The DPYD gene was found to contain 23 exons ranging in size from 69 bp (exon 15) to 961 bp (exon 23). A physical map derived from a YAC clone indicated that DPYD is at least 950 kb in length with 3 kb of coding sequence and an average intron size of about 43 kb. The previously reported 5' donor splice site mutation present in pediatric thymine-uraciluria and cancer patients can now be assigned to exon 14. All 23 exons were sequenced from a series of human DNA samples, and three point mutations were identified in three racial groups as G1601A (exon 13, Ser534Asn), A1627G (exon 13, Ile543Val), and G2194A (exon 18, Val732Ile). These studies, which have established that the DPYD gene is unusually large, lay a framework for uncovering new mutations that are responsible for thymine-uraciluria and toxicity to fluoropyrimidine drugs.
二氢嘧啶脱氢酶（DPD）可分解内源性嘧啶和基于嘧啶的抗代谢药物。人类DPD缺乏与儿科患者的先天性胸腺嘧啶 - 尿嘧啶尿症以及癌症患者严重的5 - 氟尿嘧啶毒性有关。二氢嘧啶脱氢酶基因（DPYD）已被分离出来，通过对P1、PAC、BAC和YAC克隆的分析确定了其物理图谱和外显子 - 内含子组织。发现DPYD基因包含23个外显子，大小从69 bp（外显子15）到961 bp（外显子23）不等。源自YAC克隆的物理图谱表明，DPYD长度至少为950 kb，编码序列为3 kb，平均内含子大小约为43 kb。先前报道的儿科胸腺嘧啶 - 尿嘧啶尿症和癌症患者中存在的5'供体剪接位点突变现在可定位到外显子14。从一系列人类DNA样本中对所有23个外显子进行了测序，并在三个种族群体中鉴定出三个点突变，分别为G1601A（外显子13，Ser534Asn）、A1627G（外显子13，Ile543Val）和G2194A（外显子18，Val732Ile）。这些研究确定了DPYD基因异常大，为揭示导致胸腺嘧啶 - 尿嘧啶尿症和对氟嘧啶药物毒性的新突变奠定了框架。
