Characterization of the human dihydropyrimidine dehydrogenase gene
Characterization of the human dihydropyrimidine dehydrogenase gene
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DOI：
10.1006/geno.1998.5379
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发表时间：
1998-08-01
期刊：
影响因子：
4.4
通讯作者：
Gonzalez, FJ
中科院分区：
文献类型：
--
作者：
Wei, XX;Elizondo, G;Gonzalez, FJ
二氢嘧啶脱氢酶（DPD）分解代谢内源性嘧啶和基于嘧啶的抗代谢药物。人DPD缺乏与儿科患者的先天性胸腺嘧啶尿嘧啶和癌症患者的严重5-氟尿嘧啶毒性有关。分离二氢嘧啶脱氢酶基因（DPYD），并通过分析P1、PAC、BAG和YAC克隆确定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）。来自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，以前报道的5'供体剪接位点突变存在于小儿胸腺嘧啶尿症和癌症患者现在可以分配到外显子14。对一系列人类DNA样本的所有23个外显子进行测序，在三个种族组中鉴定出三个点突变，分别为G1601 A（外显子13，Ser 534 Asn），A1627 G（外显子13，Ile 543 Val）和G2194 A（外显子18，Val 732 Ile）。这些研究已经确定DPYD基因异常大，为发现导致胸腺嘧啶尿嘧啶和氟嘧啶药物毒性的新突变奠定了框架。(C)1998学术出版社
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, BAG, 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. (C) 1998 Academic Press