Pm. Fernandezsalguero et al., LACK OF CORRELATION BETWEEN PHENOTYPE AND GENOTYPE FOR THE POLYMORPHICALLY EXPRESSED DIHYDROPYRIMIDINE DEHYDROGENASE IN A FAMILY OF PAKISTANI ORIGIN, Pharmacogenetics, 7(2), 1997, pp. 161-163
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.