Dihydropyrimidinase Deficiency: Structural Organization, Chromosomal Localization, and Mutation Analysis of the Human Dihydropyrimidinase Gene

Abstract

Dihydropyrimidinase (DHP) deficiency (MIM 222748) is characterized by dihydropyrimidinuria and is associated with a variable clinical phenotype. This disease might be associated with a risk of 5-fluorouracil toxicity, although no cases have been reported. We present here both the molecular characterization of the human DHP gene and, for the first time, the mutations causing DHP deficiency. The human DHP gene spans >80 kb and consists of 10 exons. It has been assigned to 8q22, by FISH. We performed mutation analysis of genomic DNA in one symptomatic and five asymptomatic individuals presenting with dihydropyrimidinuria. We identified one frameshift mutation and five missense mutations. Two related Japanese adult subjects were homozygous for the Q334R substitution, whereas two other, unrelated Japanese infant subjects were heterozygous for the same mutation, but this mutation is not common in the Japanese population. A Caucasian pediatric patient exhibiting epileptic attacks, dysmorphic features, and severe developmental delay was homozygous for W360R. Using a eukaryotic expression system, we showed that all mutations reduced enzyme activity significantly, indicating that these are crucial DHP deficiency-causing mutations. There was no significant difference, in residual activity, between mutations observed in the symptomatic and those observed in the asymptomatic individuals.

Genetic factors influencing Pyrimidine-antagonist chemotherapy

“…Missense mutation G883A in exon 5 has been associated with severe 5-FU toxicity. 58 This mutation has been shown to result in mutant DHP enzyme without residual activity.…”

Dihydropyrimidinase Deficiency: The First Feline Case of Dihydropyrimidinuria with Clinical and Molecular Findings

“…However, some of the control cats possessed the deletion homozygously or heterozygously, suggesting it is a polymorphism. The p.G435R (c.1303G>A) mutation was previously reported in an asymptomatic human patient with DHPuria, although it was found to be compound heterozygous with the p.Q334R mutation (Hamajima et al 1998). Expression analysis of the human p.G435R mutation in COS-7 cells revealed that it exhibits severely reduced enzymatic activity, demonstrating that p.G435R is a DHP deficiency-causing mutation.…”

“…The scientific reason why 5-FU is severely toxic to cats has yet to be clarified, but it may be due to a lower catabolic rate in the breakdown pathway for pyrimidine bases than other species. Therefore, without any medication such as 5-FU, the affected cat is symptomatic due to the p.G435R mutation, which is less deleterious and does not cause a symptomatic DHP deficiency in humans (Hamajima et al 1998). …”

“…Currently, only 28 patients have been described with DHP deficiency caused by autosomal recessive defects of the DPYS gene (OMIM 222748), and 5 of these patients were symptomless individuals who were identified by a screening program (Assmann et al 1997;Duran et al 1990Duran et al , 1991Hamajima et al 1998;Henderson et al 1993;Ohba et al 1994;Putman et al 1997;Sumi et al 1996Sumi et al , 1998Van Gennip et al 1997;Van Kuilenburg et al 2007. The prevalence of human DHP deficiency in Japan has been estimated to be 1 in 10,000.…”

Diagnosis of dihydropyrimidinase deficiency in a Chinese boy with dihydropyrimidinuria

“…1 The human DHP gene, DPYS, has been mapped to chromosome 8q22 by fluorescence in-situ hybridisation, and consists of 10 exons spanning more than 80 kb in the human genome. 2 Dihydropyrimidinase deficiency (MIM 222748) is an autosomal recessive inborn error of pyrimidine metabolism characterised by the presence of dihydropyrimidinuria. The first case of DHP deficiency was first reported by Duran et al 3 The patient was a Turkish male infant presenting with convulsion at 8 weeks after birth; at age 19 months the child appeared to be normal.…”