Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity
Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity
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DOI：
10.1172/jci118830
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发表时间：
1996-08-01
影响因子：
15.9
通讯作者：
FernandezSalguero, P
中科院分区：
文献类型：
--
作者：
Wei, XX;McLeod, HL;FernandezSalguero, P
二氢嘧啶脱氢酶（DPD）缺乏症是一种先天性嘧啶代谢缺陷，与儿科患者的胸腺嘧啶尿嘧啶相关，并增加了接受5-氟尿嘧啶（5-FU）治疗的癌症患者的毒性风险。DPD缺乏症的分子基础，在英国家庭有一个癌症患者表现出IV级毒性5-FU治疗后10天进行了分析。一个165 bp的缺失跨越一个完整的外显子DPYD基因被发现在一些成员的系谱具有低DPD催化活性。对这些受试者的淋巴细胞DNA进行直接测序，结果显示在5 '剪接位点共有序列（GT至AT）处存在G至A点突变，导致前体RNA转录和加工期间突变前的整个外显子跳跃。开发了一种基于PCR的诊断方法，以确定在高加索人和亚洲人群中发现的突变。这种突变也被检测到在荷兰患者胸腺嘧啶尿嘧啶和完全缺乏DPD活性。G至A剪接点突变的基因分型检测可用于预测癌症患者在给予潜在毒性的5-FU后易发生毒性，并用于杂合子携带者和纯合子缺陷受试者的遗传筛查。
Dihydropyrimidine dehydrogenase (DPD) deficiency constitutes an inborn error in pyrimidine metabolism associated with thymine-uraciluria in pediatric patients and an increased risk of toxicity in cancer patients receiving 5-fluorouracil (5-FU) treatment. The molecular basis for DPD deficiency in a British family having a cancer patient that exhibited grade IV toxicity 10 d after 5-FU treatment was analyzed. A 165-bp deletion spanning a complete exon of the DPYD gene was found in some members of the pedigree having low DPD catalytic activity. Direct sequencing of lymphocyte DNA from these subjects revealed the presence of a G to A point mutation at the 5'-splicing site consensus sequence (GT to AT) that leads to skipping of the entire exon preceding the mutation during pre-RNA transcription and processing. A PCR-based diagnostic method was developed to determine that the mutation is found in Caucasian and Asian populations. This mutation was also detected in a Dutch patient with thymine-uraciluria and completely lacking DPD activity. A genotyping test for the G to A splicing point mutation could be useful in predicting cancer patients prone to toxicity upon administration of potentially toxic 5-FU and for genetic screening of heterozygous carriers and homozygous deficient subjects.