A case of xanthinuria type I with a novel mutation in xanthine dehydrogenase

Iguchi, Akira; Sato, Takaaki; Yamazaki, Mitsuhiro; Tasaki, Kazuyuki; Suzuki, Yasushi; Iino, Noriaki; Hasegawa, Hiroshi; Ichida, Kimiyoshi; Narita, Ichiei

doi:10.1007/s13730-016-0216-3

Cited by 14 publications

(13 citation statements)

References 24 publications

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“…Xanthine urolithiasis is rare in domestic species and in humans . Iatrogenic xanthine uroliths have been reported in dogs treated with allopurinol, an XDH inhibitor .…”

Section: Discussionmentioning

confidence: 99%

Hereditary xanthinuria in a goat

Vail

Tate

Likavec

et al. 2019

Veterinary Internal Medicne

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A 2‐year‐old mixed breed goat was presented for a 1‐day history of anorexia and 1 week of weight loss. Serum biochemistry disclosed severe azotemia. Abdominal ultrasound examination showed decreased renal corticomedullary distinction, poor visualization of the renal pelves, and dilated ureters. On necropsy, the kidneys were small, the pelves were dilated, and the medulla was partially effaced by variably sized yellow nephroliths. Histologically, cortical and medullary tubules were distended by yellow‐brown, multilayered crystals. Stone composition was 100% xanthine. Exonic sequencing of xanthine dehydrogenase (XDH) and molybdenum cofactor sulfurase (MOCOS) identified 2 putative pathogenic variants: a heterozygous XDH p.Leu128Pro variant and a homozygous MOCOS p.Asp303Gly variant. Variant frequencies were determined in 7 herd mates, 12 goats undergoing necropsy, and 443 goats from genome databases. The XDH variant was not present in any of these 462 goats. The MOCOS variant allele frequency was 0.03 overall, with 3 homozygotes detected. Hereditary xanthinuria is a recessive disorder in other species, but the XDH variant could be causal if the case goat is a compound heterozygote harboring a second variant in a regulatory region not analyzed or if the combination of the XDH and MOCOS variants together abolish XDH activity. Alternatively, the MOCOS variant alone could be causal despite the presence of other homozygotes, because hereditary xanthinuria in humans often is asymptomatic. Ours is the first report describing the clinical presentation and pathology associated with xanthine urolithiasis in a goat. The data support hereditary xanthinuria, but functional studies are needed to conclusively determine the causal variant(s).

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“…Xanthine urolithiasis is rare in domestic species and in humans . Iatrogenic xanthine uroliths have been reported in dogs treated with allopurinol, an XDH inhibitor .…”

Section: Discussionmentioning

confidence: 99%

Hereditary xanthinuria in a goat

Vail

Tate

Likavec

et al. 2019

Veterinary Internal Medicne

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“…Renal perfusion in patients with renal hypouricemia would be diminished during exercise, and reperfusion after exercise may lead to renal damage through ischemia-reperfusion injury. Unlike renal hypouricemia caused by hyperexcretion of uric acid, hypouricemia caused by low production of uric acid in hereditary xanthinuria (XOR deficiency) has not been reported to cause EIAKI [14,19,20], suggesting that XOR activity may play a role in the induction of EIAKI in patients with hypouricemia. Measurement of XOR activity may help to identify hypouricemic patients with a high risk of EIAKI.…”

Section: Discussionmentioning

confidence: 99%

“…It has been proposed that hypouricemia causes EIAKI through oxidative stress-induced spasm of the renal artery, since uric acid acts as an antioxidant to protect endothelial function [16][17][18]. Interestingly, unlike renal hypouricemia caused by hyperexcretion of uric acid, hypouricemia caused by low production of uric acid in human xanthine oxidoreductase (XOR) deficiency (hereditary xanthinuria) has not been reported to cause EIAKI [14,19,20], suggesting that XOR activity may play a role in the development of EIAKI in hypouricemia.…”

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confidence: 99%

Unexpected high plasma xanthine oxidoreductase activity in female subjects with low levels of uric acid

et al. 2018

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Hypouricemia is a high-risk factor of exercise-induced acute kidney injury (EIAKI) probably through a lack of an antioxidant effect of uric acid. Xanthine oxidoreductase (XOR) is an enzyme that catalyzes the formation of uric acid from hypoxanthine and xanthine, leading to an increase in superoxide and reactive oxygen species. Activation of XOR has been proposed to promote oxidative stress-related tissue injury. We measured plasma XOR activity by a sensitive and accurate assay using a combination of liquid chromatography and triple quadrupole mass spectrometry in subjects with relatively low levels of uric acid (≤4.0 mg/dL) who were recruited from 627 subjects (male/female: 292/335) in the Tanno-Sobetsu Study, a population-based cohort. The numbers of subjects with uric acid ≤4.0 mg/dL, ≤3.0 mg/dL and ≤2.0 mg/dL were 72 (11.5%, male/female: 5/67), 13 (2.1%, all females) and 2 (0.3%, both females), respectively. Plasma XOR activities in 5 male subjects were below the median value of the 292 male subjects. In 12 (17.9%) of the 67 female subjects with uric acid ≤4.0 mg/dL, plasma XOR activities were above the upper quartile value of the 335 female subjects. Eleven of the 12 female subjects with high plasma XOR activity and a low uric acid level had liver dysfunction and/or insulin resistance. In conclusion, unexpected high plasma XOR activities were found in some female subjects with relatively low levels of uric acid. Measurement of plasma XOR activity may help to identify hypouricemic patients with a high risk for EIAKI.

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“…Therefore, Cys residues are thought to be important for protein folding, dimer formation, and even Moco insertion [ 24 , 113 ]. Gln102Arg, a missense mutation between Fe/SI and Fe/SII ( Figure 7 A), is thought to alter the electrostatic environment by substituting arginine with a stronger charge, which may disrupt the structure of the Fe/S cluster and cause misfolding [ 96 ].…”

Section: Detected Genetic Abnormalitiesmentioning

confidence: 99%

Association of Mutations Identified in Xanthinuria with the Function and Inhibition Mechanism of Xanthine Oxidoreductase

Sekine

Ichida

2021

Biomedicines

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Xanthine oxidoreductase (XOR) is an enzyme that catalyzes the two-step reaction from hypoxanthine to xanthine and from xanthine to uric acid in purine metabolism. XOR generally carries dehydrogenase activity (XDH) but is converted into an oxidase (XO) under various pathophysiologic conditions. The complex structure and enzymatic function of XOR have been well investigated by mutagenesis studies of mammalian XOR and structural analysis of XOR–inhibitor interactions. Three XOR inhibitors are currently used as hyperuricemia and gout therapeutics but are also expected to have potential effects other than uric acid reduction, such as suppressing XO–generating reactive oxygen species. Isolated XOR deficiency, xanthinuria type I, is a good model of the metabolic effects of XOR inhibitors. It is characterized by hypouricemia, markedly decreased uric acid excretion, and increased serum and urinary xanthine concentrations, with no clinically significant symptoms. The pathogenesis and relationship between mutations and XOR activity in xanthinuria are useful for elucidating the biological role of XOR and the details of the XOR reaction process. In this review, we aim to contribute to the basic science and clinical aspects of XOR by linking the mutations in xanthinuria to structural studies, in order to understand the function and reaction mechanism of XOR in vivo.

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A case of xanthinuria type I with a novel mutation in xanthine dehydrogenase

Cited by 14 publications

References 24 publications

Hereditary xanthinuria in a goat

Hereditary xanthinuria in a goat

Unexpected high plasma xanthine oxidoreductase activity in female subjects with low levels of uric acid

Association of Mutations Identified in Xanthinuria with the Function and Inhibition Mechanism of Xanthine Oxidoreductase

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