Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity

被引:277
作者
Wei, XX
McLeod, HL
McMurrough, J
Gonzalez, FJ
FernandezSalguero, P
机构
[1] NCI,MOL CARCINOGENESIS LAB,NIH,BETHESDA,MD 20892
[2] UNIV ABERDEEN,DEPT MED & THERAPEUT,ABERDEEN AB9 2ZD,SCOTLAND
基金
英国惠康基金;
关键词
DPD deficiency; 5-FU toxicity; population genotyping; exon skipping;
D O I
10.1172/JCI118830
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:610 / 615
页数:6
相关论文
共 29 条
[1]   ELEVATED URINE, BLOOD AND CEREBROSPINAL-FLUID LEVELS OF URACIL AND THYMINE IN A CHILD WITH DIHYDROTHYMINE DEHYDROGENASE-DEFICIENCY [J].
BAKKEREN, JAJM ;
DEABREU, RA ;
SENGERS, RCA ;
GABREELS, FJM ;
MAAS, JM ;
RENIER, WO .
CLINICA CHIMICA ACTA, 1984, 140 (03) :247-256
[2]   DIHYDROPYRIMIDINE DEHYDROGENASE-DEFICIENCY LEADING TO THYMINE-URACILURIA - AN INBORN ERROR OF PYRIMIDINE METABOLISM [J].
BERGER, R ;
STOKERDEVRIES, SA ;
WADMAN, SK ;
DURAN, M ;
BEEMER, FA ;
DEBREE, PK ;
WEITSBINNERTS, JJ ;
PENDERS, TJ ;
VANDERWOUDE, JK .
CLINICA CHIMICA ACTA, 1984, 141 (2-3) :227-234
[3]   EXON RECOGNITION IN VERTEBRATE SPLICING [J].
BERGET, SM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (06) :2411-2414
[4]  
BROCKSTED M, 1990, J INHERIT METAB DIS, V8, P115
[5]  
CHABNER BA, 1985, CANCER PRINCIPLES PR, P287
[6]   SINGLE-STEP METHOD OF RNA ISOLATION BY ACID GUANIDINIUM THIOCYANATE PHENOL CHLOROFORM EXTRACTION [J].
CHOMCZYNSKI, P ;
SACCHI, N .
ANALYTICAL BIOCHEMISTRY, 1987, 162 (01) :156-159
[7]  
COLE WG, 1990, J BIOL CHEM, V265, P17070
[8]   FAMILIAL DEFICIENCY OF DIHYDROPYRIMIDINE DEHYDROGENASE - BIOCHEMICAL BASIS FOR FAMILIAL PYRIMIDINEMIA AND SEVERE 5-FLUOROURACIL-INDUCED TOXICITY [J].
DIASIO, RB ;
BEAVERS, TL ;
CARPENTER, JT .
JOURNAL OF CLINICAL INVESTIGATION, 1988, 81 (01) :47-51
[9]   CORRELATION BETWEEN CATALYTIC ACTIVITY AND PROTEIN-CONTENT FOR THE POLYMORPHICALLY EXPRESSED DIHYDROPYRIMIDINE DEHYDROGENASE IN HUMAN-LYMPHOCYTES [J].
FERNANDEZSALGUERO, P ;
GONZALEZ, FJ ;
ETIENNE, MC ;
MILANO, G ;
KIMURA, S .
BIOCHEMICAL PHARMACOLOGY, 1995, 50 (07) :1015-1020
[10]  
FERNANDEZSALGUERO P, 1995, AM J HUM GENET, V57, P651