Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females

Zikánová, Marie; Wahezi, Dawn M.; Hay, Arielle; Stibůrková, Blanka; Pitts, C. W.; Musalkova, Dita; Škopová, Václava; Barešová, Veronika; Souckova, Olga; Hodaňová, Kateřina; Živná, Martina; Stránecký, Viktor; Hartmannová, Hana; Hnı́zda, Aleš; Bleyer, Anthony J.; Kmoch, Stanislav

doi:10.1093/rheumatology/key041

Cited by 13 publications

(8 citation statements)

References 17 publications

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“…Gout usually occurs between the fourth and sixth decade of life. Pediatric-onset of hyperuricemia and gout in clinical practice is rare and suggestive of a genetic disorder as PRPS1 superactivity [ 5 ] and hypoxanthine-guanine phosphoribosyltransferase deficiency [ 6 ], especially when a strong family history is obtained.…”

Section: Introductionmentioning

confidence: 99%

The impact of dysfunctional variants of ABCG2 on hyperuricemia and gout in pediatric-onset patients

et al. 2019

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BackgroundABCG2 is a high-capacity urate transporter that plays a crucial role in renal urate overload and extra-renal urate underexcretion. Previous studies have suggested an association between hyperuricemia and gout susceptibility relative to dysfunctional ABCG2 variants, with rs2231142 (Q141K) being the most common. In this study, we analyzed the ABCG2 gene in a hyperuricemia and gout cohort focusing on patients with pediatric-onset, i.e., before 18 years of age.MethodThe cohort was recruited from the Czech Republic (n = 234) and consisted of 58 primary hyperuricemia and 176 gout patients, with a focus on pediatric-onset patients (n = 31, 17 hyperuricemia/14 gouts); 115 normouricemic controls were used for comparison. We amplified, sequenced, and analyzed 15 ABCG2 exons. The chi-square goodness-of-fit test was used to compare minor allele frequencies (MAF), and the log-rank test was used to compare empirical distribution functions.ResultsIn the pediatric-onset cohort, two common (p.V12M, p.Q141K) and three very rare (p.K360del, p.T421A, p.T434M) allelic ABCG2 variants were detected. The MAF of p.Q141K was 38.7% compared to adult-onset MAF 21.2% (OR = 2.4, P = 0.005), to the normouricemic controls cohort MAF 8.5% (OR = 6.8, P < 0.0001), and to the European population MAF 9.4% (OR = 5.7, P < 0.0001). The MAF was greatly elevated not only among pediatric-onset gout patients (42.9%) but also among patients with hyperuricemia (35.3%). Most (74%) of the pediatric-onset patients had affected family members (61% were first-degree relatives).ConclusionOur results show that genetic factors affecting ABCG2 function should be routinely considered in a hyperuricemia/gout diagnosis, especially in pediatric-onset patients. Genotyping of ABCG2 is essential for risk estimation of gout/hyperuricemia in patients with very early-onset and/or a family history.

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Section: Introductionmentioning

confidence: 99%

The impact of dysfunctional variants of ABCG2 on hyperuricemia and gout in pediatric-onset patients

et al. 2019

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“…Thus, the down‐regulation of PRPS1 might disturb kidney recovery. Furthermore, a previous study reported that PRPS1 superactivity was a rare X‐linked disorder, and that when PRPS1 activity was increased, it resulted in an increase in purine production . Therefore, it was speculated that the purine production was decreased in the present study.…”

Section: Resultsmentioning

confidence: 67%

Proteomic analysis of rat kidney under maleic acid treatment by SWATH‐MS technology

Chien

Xue

Chen

et al. 2020

Rapid Comm Mass Spectrometry

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Rationale Maleic acid is an industrial‐grade chemical that is often used in adhesives, stabilizers, and preservatives. It is unknown whether long‐term consumption of maleic acid modified starch is harmful to humans. However, many studies have indicated that maleic acid causes renal tubular damage in animal models, even as the associated pathways remain unclear. Sequential window acquisition of all theoretical fragment ion spectra (SWATH) is the most innovative of the label‐free quantitative technologies which have better quantification performance. Therefore, SWATH technology was used to investigate the effect of maleic acid on the rat kidney proteome in this study. Methods Sprague‐Dawley(SD) rats were treated with 0 mg/kg (control), 6 mg/kg (low‐dose), 10 mg/kg (medium‐dose), and 60 mg/kg (high‐dose) of maleic acid. After kidney protein extraction, 28% SDS‐PAGE was used, followed by in‐gel digestion and desalting. Next, the samples were analyzed with ultra‐performance liquid chromatography (UPLC) coupled with quadrupole time‐of‐flight mass spectrometry (Q‐TOF MS), and data‐dependent acquisition (DDA) and SWATH technology were also used. The gene ontology and pathway analysis were accomplished. Ultimately, these protein biomarkers were validated by using scheduled high‐resolution multiple reaction monitoring (sMRMHR). Results Comparisons of the control group with the other three groups revealed that 95, 130, and 103 proteins were expressed at significantly different levels in the control group and in the low‐dose, medium‐dose, and high‐dose groups, respectively. According to the gene ontology analysis, the major processes that these proteins were involved in were metabolic processes, biological regulation, cellular processes, and responses to stimuli; the major functions that these proteins were involved in were binding, hydrolase activity, catalytic activity, and oxidoreductase activity; and the major cellular components hat they were involved in were the cytoplasm, extracellular region, membrane, and mitochondria. According to the KEGG pathway analysis, these proteins were involved in 35 pathways, five of which, the carbohydrate metabolism, folate biosynthesis, renal tubular resorption, amino acid metabolism, and Ras signaling pathways, are discussed in this study. Ultimately, 19 proteins involved in 12 important pathways were validated by sMRMHR. Conclusions It was demonstrated that maleic acid caused insufficient energy production, which might lead to a decrease in the activity of the sodium‐potassium ATP pump and hydrogen ion ATP pump, which could in turn have caused renal tubular resorption and hydrogen ion regulation to be blocked, thus leading to the accumulation of hydrogen ions in the renal tubules, which would then result in renal tubular acidification followed finally by Fanconi syndrome.

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“…Patients with severe or extremely high PRPS1 superactivity may exhibit one or more of the following nine missense PRPS1 mutations, p.D52H (c.154G > C), p.L129I (c.385C > A), p.A190V (c.569C > T), p.H193Q (c.579C > G) [ 151 ], p.N114S (c.341A > G) and p.D183H (c.547G > C) [ 118 , 151 ], p.H193L (c.578A > T) [ 150 , 151 ], p.G174V (c.521G > T) [ 162 ] and p. G174R (c.520G > A) [ 163 ]. Specifically, the missense mutations of p.D52H and p.L129I result in the disruption of local structure close to the allosteric sites and therefore inhibit feedback regulation [ 118 , 151 , 164 ].…”

Section: Human Prps and Associated Disordersmentioning

confidence: 99%

“…In males, PRPS1 superactivity resulted in an alteration in the allosteric control of PRPP synthesis with high purine nucleotide and uric acid production [ 17 ]. However, the study of Zikánová et al (2018) [ 163 ] showed that female carriers of PRPS1 superactivity had elevated levels of uric acid and gout since random X-chromosome inactivation may result in them retaining only the mutated allele p.G174R (c.520G > C).…”

Section: Human Prps and Associated Disordersmentioning

confidence: 99%

Contribution of Model Organisms to Investigating the Far-Reaching Consequences of PRPP Metabolism on Human Health and Well-Being

Ugbogu

Schweizer

2022

Cells

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Phosphoribosyl pyrophosphate synthetase (PRS EC 2.7.6.1) is a rate-limiting enzyme that irreversibly catalyzes the formation of phosphoribosyl pyrophosphate (PRPP) from ribose-5-phosphate and adenosine triphosphate (ATP). This key metabolite is required for the synthesis of purine and pyrimidine nucleotides, the two aromatic amino acids histidine and tryptophan, the cofactors nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+), all of which are essential for various life processes. Despite its ubiquity and essential nature across the plant and animal kingdoms, PRPP synthetase displays species-specific characteristics regarding the number of gene copies and architecture permitting interaction with other areas of cellular metabolism. The impact of mutated PRS genes in the model eukaryote Saccharomyces cerevisiae on cell signalling and metabolism may be relevant to the human neuropathies associated with PRPS mutations. Human PRPS1 and PRPS2 gene products are implicated in drug resistance associated with recurrent acute lymphoblastic leukaemia and progression of colorectal cancer and hepatocellular carcinoma. The investigation of PRPP metabolism in accepted model organisms, e.g., yeast and zebrafish, has the potential to reveal novel drug targets for treating at least some of the diseases, often characterized by overlapping symptoms, such as Arts syndrome and respiratory infections, and uncover the significance and relevance of human PRPS in disease diagnosis, management, and treatment.

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Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females

Cited by 13 publications

References 17 publications

The impact of dysfunctional variants of ABCG2 on hyperuricemia and gout in pediatric-onset patients

The impact of dysfunctional variants of ABCG2 on hyperuricemia and gout in pediatric-onset patients

Proteomic analysis of rat kidney under maleic acid treatment by SWATH‐MS technology

Contribution of Model Organisms to Investigating the Far-Reaching Consequences of PRPP Metabolism on Human Health and Well-Being

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