Xanthine Nephrolithiasis in a Galician Blond Beef Calf

Miranda, Marta; Rigueira, Lucas; Suárez, Marta; Carbajales, Paloma; Moure, P.; Fidalgo, Luis Eusebio; Faílde, Daniel; Vázquez, S.

doi:10.1292/jvms.09-0494

Cited by 9 publications

(12 citation statements)

References 12 publications

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“…deformity or overgrowth of hooves have been previously reported in cases of renal dysplasia in cattle [6, 10]. In papers describing xanthinuria in cattle, it was not possible to find reports of overgrown hooves [14, 15], but such features could be an indicator of a general sign of renal failure (along with poor growth) and not of a specific disease. The very limited number of cases prevents us from observing in detail how the position and specific nature of the mutation affect the onset and severity of xanthinuria.…”

Section: Resultsmentioning

confidence: 99%

“…This autosomal recessive inherited disease has been associated with a 3 bp deletion in the coding region of the molybdenum cofactor sulfurase ( MOCOS ) gene . In a single genetically uncharacterized Galician Blond beef calf, signs of listlessness and weight loss and renal failure with bilateral nephrolithiasis, composed of 100% xanthine were reported [15]. …”

Section: Introductionmentioning

confidence: 99%

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A frameshift mutation in MOCOS is associated with familial renal syndrome (xanthinuria) in Tyrolean Grey cattle

Murgiano

Jagannathan

Piffer³

et al. 2016

BMC Vet Res

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BackgroundRenal syndromes are occasionally reported in domestic animals. Two identical twin Tyrolean Grey calves exhibited weight loss, skeletal abnormalities and delayed development associated with kidney abnormalities and formation of uroliths. These signs resembled inherited renal tubular dysplasia found in Japanese Black cattle which is associated with mutations in the claudin 16 gene. Despite demonstrating striking phenotypic similarities, no obvious presence of pathogenic variants of this candidate gene were found. Therefore further analysis was required to decipher the genetic etiology of the condition.ResultsThe family history of the cases suggested the possibility of an autosomal recessive inheritance. Homozygosity mapping combined with sequencing of the whole genome of one case detected two associated non-synonymous private coding variants: A homozygous missense variant in the uncharacterized KIAA2026 gene (g.39038055C > G; c.926C > G), located in a 15 Mb sized region of homozygosity on BTA 8; and a homozygous 1 bp deletion in the molybdenum cofactor sulfurase (MOCOS) gene (g.21222030delC; c.1881delG and c.1782delG), located in an 11 Mb region of homozygosity on BTA 24. Pathogenic variants in MOCOS have previously been associated with inherited metabolic syndromes and xanthinuria in different species including Japanese Black cattle. Genotyping of two additional clinically suspicious cases confirmed the association with the MOCOS variant, as both animals had a homozygous mutant genotype and did not show the variant KIAA2026 allele. The identified genomic deletion is predicted to be highly disruptive, creating a frameshift and premature termination of translation, resulting in severely truncated MOCOS proteins that lack two functionally essential domains. The variant MOCOS allele was absent from cattle of other breeds and approximately 4% carriers were detected among more than 1200 genotyped Tyrolean Grey cattle. Biochemical urolith analysis of one case revealed the presence of approximately 95% xanthine.ConclusionsThe identified MOCOS loss of function variant is highly likely to cause the renal syndrome in the affected animals. The results suggest that the phenotypic features of the renal syndrome were related to an early onset form of xanthinuria, which is highly likely to lead to the progressive defects. The identification of the candidate causative mutation thus enables selection against this pathogenic variant in Tyrolean Grey cattle.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-016-0904-4) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A frameshift mutation in MOCOS is associated with familial renal syndrome (xanthinuria) in Tyrolean Grey cattle

Murgiano

Jagannathan

Piffer³

et al. 2016

BMC Vet Res

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“…Specifically, a study on sheep with xanthine calculi concluded that low dietary molybdenum could be causative because of molybdenum's role in purine metabolism . Hereditary xanthinuria has been reported in cats (OMIA 001283‐9685), dogs (OMIA 001283‐9615), and cattle (OMIA 001819‐9913) . In some reports, the genetic basis was established by sequencing; in other cases, a primary cause was presumed after eliminating a history of XDH inhibitor use .…”

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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“…In higher animals other than primates, xanthinuria is lethal due to kidney damage resulting from xanthine stones in the urinary tract [28–30], and this is explained by an acquired tolerance to oxypurines by primates that followed the loss of uricase during evolution [31]. …”

Section: Discussionmentioning

confidence: 99%

The renal phenotype of allopurinol-treated HPRT-deficient mouse

et al. 2017

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Excess of uric acid is mainly treated with xanthine oxidase (XO) inhibitors, also called uricostatics because they block the conversion of hypoxanthine and xanthine into urate. Normally, accumulation of upstream metabolites is prevented by the hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme. The recycling pathway, however, is impaired in the presence of HPRT deficiency, as observed in Lesch-Nyhan disease. To gain insights into the consequences of purine accumulation with HPRT deficiency, we investigated the effects of the XO inhibitor allopurinol in Hprt-lacking (HPRT-/-) mice. Allopurinol was administered in the drinking water of E12-E14 pregnant mothers at dosages of 150 or 75 μg/ml, and mice sacrificed after weaning. The drug was well tolerated by wild-type animals and heterozygous HPRT+/- mice. Instead, a profound alteration of the renal function was observed in the HPRT-/- model. Increased hypoxanthine and xanthine concentrations were found in the blood. The kidneys showed a yellowish appearance, diffuse interstitial nephritis, with dilated tubules, inflammatory and fibrotic changes of the interstitium. There were numerous xanthine tubular crystals, as determined by HPLC analysis. Oil red O staining demonstrated lipid accumulation in the same location of xanthine deposits. mRNA analysis showed increased expression of adipogenesis-related molecules as well as profibrotic and proinflammatory pathways. Immunostaining showed numerous monocyte-macrophages and overexpression of alpha-smooth muscle actin in the tubulointerstitium. In vitro, addition of xanthine to tubular cells caused diffuse oil red O positivity and modification of the cell phenotype, with loss of epithelial features and appearance of mesenchymal characteristics, similarly to what was observed in vivo. Our results indicate that in the absence of HPRT, blockade of XO by allopurinol causes rapidly developing renal failure due to xanthine deposition within the mouse kidney. Xanthine seems to be directly involved in promoting lipid accumulation and subsequent phenotype changes of tubular cells, with activation of inflammation and fibrosis.

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Xanthine Nephrolithiasis in a Galician Blond Beef Calf

Cited by 9 publications

References 12 publications

A frameshift mutation in MOCOS is associated with familial renal syndrome (xanthinuria) in Tyrolean Grey cattle

A frameshift mutation in MOCOS is associated with familial renal syndrome (xanthinuria) in Tyrolean Grey cattle

Hereditary xanthinuria in a goat

The renal phenotype of allopurinol-treated HPRT-deficient mouse

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