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

Chang, Hye-Sook; Shibata, Takayuki; Arai, Satoshi; Zhang, Chunhua; Yabuki, Akira; Mitani, Sawane; Higo, Tomoya; Sunagawa, K.; Mizukami, Keijiro; Yamato, Osamu

doi:10.1007/8904_2012_139

Cited by 10 publications

(8 citation statements)

References 17 publications

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“…The DPYS gene encodes DHP which is the second enzyme in the catabolic pathway of pyrimidines [23]. Mutations in the DPYS gene can cause DHP deficiency, which is a rare inborn error of the pyrimidine degradation pathway [24].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…There are three defects associated with pyrimidines, namely dihydropyrimidine dehydrogenase, dihydropyrimidinase and 3-ureidopropionase deficiencies (42,43). There are numerous purine-associated disorders, including orotic aciduria (44,45).…”

Section: Discussionmentioning

confidence: 99%

Novel two-step derivation method for the synchronous analysis of inherited metabolic disorders using urine

Sheng

Wang

2017

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to conduct preliminary clinical screening and monitoring using a novel two-step derivatization process of urine in five categories of inherited metabolic disease (IMD). Urine samples (100 µl, containing 2.5 mmol/l creatinine) were taken from patients with IMDs. The collected urine was then treated using a two-step derivatization method (with oximation and silylation at room temperature), where urea and protein were removed. In the first step of the derivatization, α-ketoacids and α-aldehyde acids were prepared by oximation using novel oximation reagents. The second-step of the derivatization was that residues were silylated for analysis. Urine samples were examined using gas chromatography/mass spectrometry (GC/MS) and a retention time-locking technique. The simultaneous analysis and identification of >400 metabolites in >130 types of IMD was possible from the GC/MS results, where the IMDs included phenylketonuria, ornithine transcarbamylase deficiency, neonatal intrahepatic cholestasis caused by citrin deficiency, β-ureidopropionase deficiency and mitochondrial metabolic disorders. This method was demonstrated to have good repeatability. Considering α-ketoglutarate (α-KG) as an example, the relative standard deviations (RSDs) of the α-KG retention time and peak area were 0.8 and 3.9%, respectively, the blank spiked recovery rate was between 89.6 and 99.8%, and the RSD was ≤7.5% (n=5). The method facilitates the analysis of thermally non-stable and semi-volatile metabolites in urine, and greatly expands the range of materials that can be synchronously screened by GC/MS. Furthermore, it provides a comprehensive, effective and reliable biochemical analysis platform for the pathological research of IMDs.

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“…To assay the blood levels of acylcarnitines, LC-MS/MS analysis was conducted as published previously (Chang et al 2012). The first sample was collected under the condition in force-feeding via a gastrostomy tube at the age of 18 months, when we start the treatment with riboflavin and L-carnitine as described above.…”

Section: Lc-ms/ms Analysismentioning

confidence: 99%

“…We assayed urine organic acids because we suspected a metabolic disorder such as dihydropyrimidinase deficiency (OMIM 222748), which has been reported in a cat exhibiting hyperammonemia (Chang et al 2012). Surprisingly, the results indicated a MADD-like profile, with increased levels of lactic acid, sarcosine, 3-hydroxybutyric acid, malonic acid, 3-hydroxyisovaleric acid, succinic acid, ethylmalonic acid, glutaric acid, isoverylglycine, 2-hydroxyglutaric acid, 3-hydroxyglutaric acid, hexonylglycine, suberic acid, sebacic acid, 3-hydroxysebacic acid, and suberylglycine (Fig.…”

Section: Feline Maddmentioning

confidence: 99%

Multiple Acyl-CoA Dehydrogenation Deficiency (Glutaric Aciduria Type II) with a Novel Mutation of Electron Transfer Flavoprotein-Dehydrogenase in a Cat

et al. 2013

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Multiple acyl-CoA dehydrogenation deficiency (MADD; also known as glutaric aciduria type II) is a human autosomal recessive disease classified as one of the mitochondrial fatty-acid oxidation disorders. MADD is caused by a defect in the electron transfer flavoprotein (ETF) or ETF dehydrogenase (ETFDH) molecule, but as yet, inherited MADD has not been reported in animals. Here we present the first report of MADD in a cat. The affected animal presented with symptoms characteristic of MADD including hypoglycemia, hyperammonemia, vomiting, diagnostic organic aciduria, and accumulation of medium-and long-chain fatty acids in plasma. Treatment with riboflavin and L-carnitine ameliorated the symptoms. To detect the gene mutation responsible for MADD in this case, we determined the complete cDNA sequences of feline ETFa, ETFb, and ETFDH. Finally, we identified the feline patient-specific mutation, c.692T>G (p.F231C) in ETFDH. The affected animal only carries mutant alleles of ETFDH. p.F231 in feline ETFDH is completely conserved in eukaryotes, and is located on the apical surface of ETFDH, receiving electrons from ETF. This study thus identified the mutation strongly suspected to have been the cause of MADD in this cat.

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

Cited by 10 publications

References 17 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

Novel two-step derivation method for the synchronous analysis of inherited metabolic disorders using urine

Multiple Acyl-CoA Dehydrogenation Deficiency (Glutaric Aciduria Type II) with a Novel Mutation of Electron Transfer Flavoprotein-Dehydrogenase in a Cat

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