LACK OF CORRELATION BETWEEN PHENOTYPE AND GENOTYPE FOR THE POLYMORPHICALLY EXPRESSED DIHYDROPYRIMIDINE DEHYDROGENASE IN A FAMILY OF PAKISTANI ORIGIN

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-fluorouraci l (5-FU) treatment. DPD deficiency causes an inborn error of metabolis m called thymine-uraciluria that is in some instances associated with convulsive disorders and developmental delay in children. We have stud ied the molecular mechanism accounting for DPD deficiency in a Pakista ni pedigree having a 2-year-old child with thymine-uraciluria and exhi biting some degree of motor impairment and developmental delay. A comm on splice mutation was found in the patient's dihydropyrimidine dehydr ogenase (DPYD) gene that produces a mutant mRNA resulting in the compl ete lack of DPD protein and activity in lymphocytes and primary fibrob last. This trait segregated in the family following a typical Mendelia n distribution. Surprisingly, the patient's brother also had thymine-u raciluria and was homozygous for the splicing mutation but was clinica lly 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 resu lts suggest that DPD deficiency might not be the only cause of the mor e severe clinical phenotypes observed in certain thymine-uraciluria pa tients and that an incomplete correlation between phenotype and genoty pe is present in the population.