Lack of correlation between phenotype and genotype for the polymorphically expressed dihydropyrimidine dehydrogenase in a family of Pakistani origin

被引:26
作者
FernandezSalguero, PM
Sapone, A
Wei, XX
Holt, JR
Jones, S
Idle, JR
Gonzalez, FJ
机构
[1] NCI,MOL CARCINOGENESIS LAB,NATL INST HLTH,BETHESDA,MD 20892
[2] NCI,LAB METAB,NATL INST HLTH,BETHESDA,MD 20892
[3] MEDISINSK TEKNISK SENTER,INST CANC RES & MOL BIOL,N-7005 TRONDHEIM,NORWAY
[4] PINDERFIELDS GEN HOSP,WAKEFIELD WF1 4D6,W YORKSHIRE,ENGLAND
来源
PHARMACOGENETICS | 1997年 / 7卷 / 02期
关键词
DPD; human polymorphism; thymine-uraciluria; splice mutation;
D O I
10.1097/00008571-199704000-00012
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in pyrimidine catabolism. DPD deficiency is associated with an increased risk of toxicity in cancer patients receiving 5-fluorouracil (5-FU) treatment. DPD deficiency causes an inborn error of metabolism called thymine-uraciluria that is in some instances associated with convulsive disorders and developmental delay in children. We have studied the molecular mechanism accounting for DPD deficiency in a Pakistani pedigree having a 2-year-old child with thymine-uraciluria and exhibiting some degree of motor impairment and developmental delay. A common splice mutation was found in the patient's dihydropyrimidine dehydrogenase (DPYD) gene that produces a mutant mRNA resulting in the complete lack of DPD protein and activity in lymphocytes and primary fibroblast. This trait segregated in the family following a typical Mendelian distribution. Surprisingly, the patient's brother also had thymine-uraciluria and was homozygous for the splicing mutation but was clinically asymptomatic. Sequence tagged sites (STS) linkage analyses within 5 megabases of telomeric and centromeric DNA surrounding the DPYD gene revealed no allelic polymorphism between the two brothers. These results suggest that DPD deficiency might not be the only cause of the more severe clinical phenotypes observed in certain thymine-uraciluria patients and that an incomplete correlation between phenotype and genotype is present in the population.
引用
收藏
页码:161 / 163
页数:3
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