Diagnosis of dihydropyrimidinase deficiency in a Chinese boy with dihydropyrimidinuria

Yeung, C W; Yau, Margaret; K, C; Siu, Tak-Shing; Tam, Sidney; Lam, Christopher W.K.

doi:10.12809/hkmj133598

Cited by 13 publications

(9 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…According to the population screening for pyrimidine metabolism disorders, asymptomatic patients with complete deficiency of DHP which is caused by mutations in the DPYS gene were reported. This evidence reflects the probable effects of environmental factors in causing the clinical phenotypes [25]. Although this patient was diagnosed with DHP deficiency using accurate biochemical, genetic and bioinformatics investigations, it is difficult to prove that the clinical presentations is due to the DHP deficiency.…”

Section: Discussionmentioning

confidence: 93%

“…Mutations in the DPYS gene can cause DHP deficiency, which is a rare inborn error of the pyrimidine degradation pathway [24]. This disorder shows variable clinical manifestations including severe neurologic involvement, dysmorphic features, feeding problems, mild intellectual disability and even asymptomatic individuals [25]. In a study investigating the clinical and molecular characteristics of 17 patients with dihydropyrimidinase deficiency, the most frequent clinical features were seizure, intellectual disability and hypotonia; gastrointestinal problems were also found to be common among affected individuals [4].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A novel stop-gain mutation in DPYS gene causing Dihidropyrimidinase deficiency, a case report

et al. 2020

View full text Add to dashboard Cite

Background: Dihidropyrimidinase (DHP) deficiency is an inherited inborn error of pyrimidine metabolism with a variable clinical presentation and even asymptomatic subjects. Dihydropyrimidinase is encoded by the DPYS gene, thus pathogenic mutations in this gene can cause DHP deficiency. To date, several variations in the DPYS gene have been reported but only 23 of them have been confirmed to be pathogenic. Therefore, the biochemical, clinical and genetic aspects of this disease are still unclear. Case presentation: Here, we report a 22-year-old woman with DHP deficiency. To identify the genetic cause of DHP deficiency in this patient, Whole Exome Sequencing (WES) was performed, which revealed a novel homozygote stop gain mutation (NM_001385: Exon 9, c.1501 A > T, p.K501X) in the DPYS gene. Sanger sequencing was carried out on proband and other family members in order to confirm the identified mutation. According to the homozygote genotype of the patient and heterozygote genotype of her parents, the autosomal recessive pattern of inheritance was confirmed. In addition, bioinformatics analysis of the identified variant using Mutation Taster and T-Coffee Multiple Sequence Alignment showed the pathogenicity of mutation. Moreover, mRNA expression level of DPYS gene in the proband's liver biopsy showed about 6-fold reduction compared to control, which strongly suggested the pathogenicity of the identified mutation. Conclusions: This study identified a novel pathogenic stop gain mutation in DPYS gene in a DHP deficient patient. Our findings can improve the knowledge about the genetic basis of the disease and also provide information for accurate genetic counseling for the families at risk of these types of disorders.

show abstract

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

A novel stop-gain mutation in DPYS gene causing Dihidropyrimidinase deficiency, a case report

et al. 2020

View full text Add to dashboard Cite

show abstract

“…DHP deficiency is an autosomal recessive disease characterized by the accumulation of UH 2 and dihydrothymine (TH 2 ) in blood, urine, and cerebrospinal fluid [69]. The clinical phenotype of DHP-deficient patients is highly variable, ranging from asymptomatic to exhibiting symptomatology similar to that of DPD deficiency, including seizures, intellectual disability, growth impairment, and dysmorphic facial features [70][71][72]. To date, 35 genetically confirmed patients with DHP deficiency have been reported [33,[73][74][75][76][77].…”

Section: Dihydropyrimidinase (Dhp)mentioning

confidence: 99%

In Vitro Assessment of Fluoropyrimidine-Metabolizing Enzymes: Dihydropyrimidine Dehydrogenase, Dihydropyrimidinase, and β-Ureidopropionase

Hishinuma

Rico

Hiratsuka

2020

JCM

View full text Add to dashboard Cite

Fluoropyrimidine drugs (FPs), including 5-fluorouracil, tegafur, capecitabine, and doxifluridine, are among the most widely used anticancer agents in the treatment of solid tumors. However, severe toxicity occurs in approximately 30% of patients following FP administration, emphasizing the importance of predicting the risk of acute toxicity before treatment. Three metabolic enzymes, dihydropyrimidine dehydrogenase (DPD), dihydropyrimidinase (DHP), and β-ureidopropionase (β-UP), degrade FPs; hence, deficiencies in these enzymes, arising from genetic polymorphisms, are involved in severe FP-related toxicity, although the effect of these polymorphisms on in vivo enzymatic activity has not been clarified. Furthermore, the clinical usefulness of current methods for predicting in vivo activity, such as pyrimidine concentrations in blood or urine, is unknown. In vitro tests have been established as advantageous for predicting the in vivo activity of enzyme variants. This is due to several studies that evaluated FP activities after enzyme metabolism using transient expression systems in Escherichia coli or mammalian cells; however, there are no comparative reports of these results. Thus, in this review, we summarized the results of in vitro analyses involving DPD, DHP, and β-UP in an attempt to encourage further comparative studies using these drug types and to aid in the elucidation of their underlying mechanisms.

show abstract

“…DHPase deficiency is an autosomal recessive condition characterized by dihydropyrimidinuria (Duran et al, 1991). The clinical phenotype of DHPase-deficient patients is highly variable; while asymptomatic patients have been identified, symptoms can range from early infantile-onset of severe neurological involvement to dysmorphic features, including feeding problems and late-onset mild intellectual disability (Ohba et al, 1994;van Gennip et al, 1994;Hayashi et al, 1996;van Gennip et al, 1997;van Kuilenburg et al, 2007;van Kuilenburg et al, 2010;Yeung et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Functional Characterization of 12 Dihydropyrimidinase Allelic Variants in Japanese Individuals for the Prediction of 5-Fluorouracil Treatment-Related Toxicity

et al. 2022

View full text Add to dashboard Cite

The drug 5-fluorouracil (5-FU) is the first-choice chemotherapeutic agent against advanced-stage cancers. However, 10-30% of treated patients experience grade 3-4 toxicity. The deficiency of dihydropyrimidinase (DHPase), which catalyzes the second step of the 5-FU degradation pathway, is correlated with the risk of developing toxicity. Thus, genetic polymorphisms within DPYS, the DHPase-encoding gene, could potentially serve as predictors of severe 5-FU-related toxicity. We identified 12 novel DPYS variants in 3,554 Japanese individuals, but the effects of these mutations on function remain unknown. In the current study, we performed in vitro enzymatic analyses of the 12 newly identified DHPase variants. Dihydrouracil or dihydro-5-FU hydrolytic ring-opening kinetic parameters, K m and V max , and intrinsic clearance (CL int = V max /K m ) of the wild-type DHPase and eight variants were measured. Five of these variants (R118Q, H295R, T418I, Y448H, and T513A) showed significantly reduced CL int compared with that in the wild-type. The parameters for the remaining four variants (V59F, D81H, T136M, and R490H) could not be determined as dihydrouracil and dihydro-5-FU hydrolytic ring-opening activity was undetectable. We also determined DHPase variant protein stability using cycloheximide and bortezomib. The mechanism underlying the observed changes in the kinetic parameters was clarified

show abstract

Diagnosis of dihydropyrimidinase deficiency in a Chinese boy with dihydropyrimidinuria

Cited by 13 publications

References 11 publications

A novel stop-gain mutation in DPYS gene causing Dihidropyrimidinase deficiency, a case report

A novel stop-gain mutation in DPYS gene causing Dihidropyrimidinase deficiency, a case report

In Vitro Assessment of Fluoropyrimidine-Metabolizing Enzymes: Dihydropyrimidine Dehydrogenase, Dihydropyrimidinase, and β-Ureidopropionase

Functional Characterization of 12 Dihydropyrimidinase Allelic Variants in Japanese Individuals for the Prediction of 5-Fluorouracil Treatment-Related Toxicity

Contact Info

Product

Resources

About