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

DNA Cell Biol. 1995 Jan;14(1):1-6. doi: 10.1089/dna.1995.14.1.


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.

MeSH terms

  • Base Sequence
  • Cells, Cultured
  • Child, Preschool
  • Dihydrouracil Dehydrogenase (NADP)
  • Exons / genetics*
  • Female
  • Fibroblasts / chemistry
  • Fibroblasts / enzymology
  • Genotype
  • Humans
  • Male
  • Molecular Sequence Data
  • Netherlands
  • Oxidoreductases / deficiency*
  • Oxidoreductases / genetics*
  • Pedigree
  • Point Mutation*
  • Polymerase Chain Reaction / methods
  • Polymorphism, Genetic*
  • Purine-Pyrimidine Metabolism, Inborn Errors / enzymology
  • Purine-Pyrimidine Metabolism, Inborn Errors / ethnology
  • Purine-Pyrimidine Metabolism, Inborn Errors / genetics*
  • RNA, Messenger / analysis
  • Sequence Deletion
  • Thymine / metabolism
  • Uracil / metabolism


  • RNA, Messenger
  • Uracil
  • Oxidoreductases
  • Dihydrouracil Dehydrogenase (NADP)
  • Thymine