Alternative titles; symbols
HGNC Approved Gene Symbol: DPYS
SNOMEDCT: 238014002;
Cytogenetic location: 8q22.3 Genomic coordinates (GRCh38): 8:104,379,431-104,467,055 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q22.3 | Dihydropyrimidinuria | 222748 | Autosomal recessive | 3 |
Dihydropyrimidinase (DPYS), also known as 5,6-dihydropyrimidine amidohydrolase, or DHP (EC 3.5.2.2), is the second enzyme in the 3-step degradation pathway of uracil and thymine after the action of dihydropyramidine dehydrogenase (DPYD; 612779) (Hamajima et al., 1996).
Hamajima et al. (1996) isolated cDNA clones encoding dihydropyrimidinase from a human liver cDNA library and 3 DPYS homologs from a human fetal brain cDNA library. They termed the homologs dihydropyrimidinase-related protein (DRP)-1 (CRMP1; 602462), DRP2 (DPYSL2; 602463), and DRP3 (DPYSL3; 601168). The 519-amino acid DPYS protein sequence is 90% identical to the rat DPYS protein sequence; DRP1-3 share 57 to 59% amino acid identity with human DPYS and 74 to 77% amino acid identity with each other. Northern blot analysis of adult human tissues showed that DPYS and DRP1-3 are differentially expressed, with DPYS expressed at a high level in liver and kidney as a major 2.5-kb transcript and a minor 3.8-kb transcript. The authors discussed the relationship of the DPYS and DRP1-3 genes to similar gene sequences in other organisms.
The human DPYS gene spans more than 80 kb and comprises 10 exons. (Hamajima et al., 1998).
By fluorescence in situ hybridization, Hamajima et al. (1998) assigned the DPYS gene to chromosome 8q22.
In 1 symptomatic and 5 asymptomatic persons presenting with dihydropyrimidinuria due to DPYS deficiency (DPYSD; 222748), Hamajima et al. (1998) identified 1 frameshift mutation and 5 missense mutations in the DPYS gene (see, e.g., 613326.0001-613326.0003). Two unaffected Japanese adult sibs, who were identified by a screening program, were homozygous for a missense mutation (Q334R; 613326.0001). Two unrelated asymptomatic Japanese infants were heterozygous for the same mutation, but this mutation was not common in the Japanese. The only symptomatic patient was a Lebanese girl with dysmorphic features, developmental delay, and seizures (van Gennip et al., 1997) who was homozygous for a missense mutation (Y360R; 613326.0003). All patients had the characteristic biochemical findings of increased uracil, dihydrouracil, thymine, and dihydrothymine in bodily fluids.
Nakajima et al. (2017) identified compound heterozygous mutations in the DPYS gene, including 4 novel missense variants (see, e.g., M250I, 613326.0005 and R490H, 613326.0006) and 1 novel deletion, in 4 unrelated patients, 1 Chinese and 3 Japanese, with DPYS deficiency. Clinical presentations ranged from asymptomatic to infantile spasms with reduced white matter and brain atrophy. Nakajima et al. (2017) stated that 31 genetically confirmed patients with DPYS deficiency had been reported.
By Sanger sequencing in a Japanese boy who was incidentally found to have markedly elevated levels of dihydrouracil and dihydrothymine, Tsuchiya et al. (2019) identified compound heterozygous mutations in the DPYS gene: the previously identified R490H mutation and a novel missense mutation (V59F; 613326.0007). The parents declined genetic studies.
In 2 asymptomatic Japanese adult sibs with dihydropyrimidinase deficiency (DPYSD; 222748), Hamajima et al. (1998) found homozygosity for a 1001A-G transition in exon 6 of the DPYS gene, resulting in a gln334-to-arg (Q334R) substitution. Two other, unrelated Japanese infants were heterozygous for the same mutation; however, the mutation appeared to be uncommon in the Japanese population. A gly435-to-arg (G435R; 613326.0002) missense mutation was also detected in one of the heterozygous subjects, although whether the 2 mutations were actually on different alleles in this subject could not be definitively determined. It appeared that all of these individuals were asymptomatic. In vitro functional expression studies in COS-7 cells showed that both mutant proteins had decreased enzyme activity, but only G435R had decreased protein levels.
For discussion of the gly435-to-arg (G435R) mutation in the DPYS gene that was found in compound heterozygous state in a patient with dihydropyrimidinase deficiency (DPYSD; 222748) by Hamajima et al. (1998), see 613326.0001.
In a Lebanese girl, born of consanguineous parents, with dihydropyrimidinase deficiency (DPYSD; 222748), Hamajima et al. (1998) identified a homozygous 1078T-C transition in exon 6 of the DPYS gene, resulting in a trp360-to-arg (W360R) substitution in a conserved region at the amino-terminal end. Each unaffected parent was heterozygous for the mutation. The patient had previously been reported by van Gennip et al. (1997), and had seizures, dysmorphic features, and severe developmental delay. In vitro functional expression studies in COS-7 cells showed decreased protein levels and decreased enzyme activity. Hamajima et al. (1998) suggested that the mutation may prevent tetramerization of the protein.
In 2 Moroccan brothers with dihydropyrimidinase deficiency (DPYSD; 222748), van Kuilenburg et al. (2007) identified compound heterozygosity for 2 mutations in the DPYS gene: a 1235G-T transversion in exon 7 resulting in an arg412-to-met (R412M) substitution, and W360R (613326.0003). In vitro functional expression studies in E. coli showed no enzymatic activity for either mutation, although the mutant proteins were expressed. Structural analysis suggested that the W360R mutation would impair assembly of the tetramer, and that the R412M mutation would affect hydrogen bonding, resulting in destabilization. One of the brothers had speech delay and mild brain white matter abnormalities, whereas the other had no neurologic abnormalities.
In a Japanese girl who was identified on newborn screening to have dihydropyrimidinase deficiency (DPYSD; 222748), Nakajima et al. (2017) identified compound heterozygous mutations in the DPYS gene: a c.750G-A transition in exon 4, resulting in a met250-to-ile (M250I) substitution, and a c.1469G-A transition in exon 9, resulting in an arg490-to-his (R490H; 613326.0006) substitution. Functional analysis of recombinantly expressed DPYS mutants carrying either variant showed residual DPYS activities of 2.0% and 0.3%, respectively. Molecular modeling of DPYS indicated that the point mutations were likely to cause rearrangements of loops shaping the active site, primarily affecting the substrate binding and stability of the enzyme. At age 5.9 years, the patient was asymptomatic.
For discussion of the c.1469G-A transition in the DPYS gene, resulting in an arg490-to-his (R490H) substitution, that was found in a Japanese girl with dihydropyrimidinase deficiency (DPYS; 222748) by Nakajima et al. (2017), see 613326.0005.
By Sanger sequencing in a Japanese boy with dihydropyrimidinase deficiency (DPYS; 222748), Tsuchiya et al. (2019) identified compound heterozygous mutations in the DPYS gene: R490H (613326.0006) and a c.175G-T transversion in exon 1, resulting in a val59-to-phe substitution. The boy had markedly elevated levels of dihydrouracil and dihydrothymine. The parents declined genetic testing.
Hamajima, N., Kouwaki, M., Vreken, P., Matsuda, K., Sumi, S., Imaeda, M., Ohba, S., Kidouchi, K., Nonaka, M., Sasaki, M., Tamaki, N., Endo, Y., De Abreu, R., Rotteveel, J., van Kuilenburg, A., van Gennip, A., Togari, H., Wada, Y. Dihydropyrimidinase deficiency: structural organization, chromosomal localization, and mutation analysis of the human dihydropyrimidinase gene. Am. J. Hum. Genet. 63: 717-726, 1998. [PubMed: 9718352] [Full Text: https://doi.org/10.1086/302022]
Hamajima, N., Matsuda, K., Sakata, S., Tamaki, N., Sasaki, M., Nonaka, M. A novel gene family defined by human dihydropyrimidinase and three related proteins with differential tissue distribution. Gene 180: 157-163, 1996. [PubMed: 8973361] [Full Text: https://doi.org/10.1016/s0378-1119(96)00445-3]
Nakajima, Y., Meijer, J., Dobritzsch, D., Ito, T., Zhang, C., Wang, X., Watanabe, Y., Tashiro, K., Meinsma, R., Roelofsen, J., Zoetekouw, L, van Kuilenburg, A. B. P. Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity. Molec. Genet. Metab. 122: 216-222, 2017. [PubMed: 29054612] [Full Text: https://doi.org/10.1016/j.ymgme.2017.10.003]
Tsuchiya, H., Akiyama, T., Kuhara, T., Nakajima, N., Ohse, M., Kurahashi, H., Kato, T., Maeda, T., Yoshinaga, H., Kobayashi, K. A case of dihydropyrimidinase deficiency incidentally detected by urine metabolome analysis. Brain Dev. 41: 280-284, 2019. [PubMed: 30384990] [Full Text: https://doi.org/10.1016/j.braindev.2018.10.005]
van Gennip, A. H., de Abreu, R. A., van Lenthe, H., Bakkeren, J., Rotteveel, J., Vreken, P., van Kuilenburg, A. B. P. Dihydropyrimidinase deficiency: confirmation of the enzyme defect in dihydropyrimidinuria. J. Inherit. Metab. Dis. 20: 339-342, 1997. [PubMed: 9266350] [Full Text: https://doi.org/10.1023/a:1005309423960]
van Kuilenburg, A. B. P., Meijer, J., Dobritzsch, D., Meinsma, R., Duran, M., Lohkamp, B., Zoetekouw, L., Abeling, N. G. G. M., van Tinteren, H. L. G., Bosch, A. M. Clinical, biochemical and genetic findings in two siblings with a dihydropyrimidinase deficiency. Molec. Genet. Metab. 91: 157-164, 2007. [PubMed: 17383919] [Full Text: https://doi.org/10.1016/j.ymgme.2007.02.008]