Human polymorphism in drug metabolism: mutation in the dihydropyrimidine dehydrogenase gene results in exon skipping and thymine uracilurea.

Abstract

A condition called thymine uracilurea has been described that is due to a lack of dihydropyrimidine dehydrogenase (DPD) activity. Cancer patients experiencing acute 5-fluorouracil toxicity also have lower-than-normal DPD activities. However, to date, the molecular basis of this disorder has not been addressed. In this study, the phenotype and genotype of a family that presents a patient showing no DPD activity was determined. Fibroblast mRNAs from the patient and four family members were subjected to reverse transcriptase polymerase chain reaction (RT-PCR) using primers generated from the human DPD cDNA sequence. DPD mRNA from the patient was found to lack a segment of 165 nucleotides that results from exon skipping. DPD mRNA from the parents and a sibling were found to be heterozygous for the deleted and the normal mRNA, while a brother had two normal transcripts. DPD activities and levels of DPD protein correlated with genotype; the deficient patient had no detectable DPD protein. PCR analysis of the genomic DNA from this family revealed that the defective mRNA is not due to a deletion of a portion of the gene that contains the exon, thus implying that the mutation is the result of an as yet nonidentified point mutation that causes faulty splicing.

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@article{Meinsma1995HumanPI, title={Human polymorphism in drug metabolism: mutation in the dihydropyrimidine dehydrogenase gene results in exon skipping and thymine uracilurea.}, author={Rutger J Meinsma and Pedro M Fern{\'a}ndez-Salguero and Andr{\'e} B. P. van Kuilenburg and Albert H van Gennip and Frank J Gonzalez}, journal={DNA and cell biology}, year={1995}, volume={14 1}, pages={1-6} }