Hereditary xanthinuria in a goat

Vail, Krystal J.; Tate, Nicole M.; Likavec, Tasha; Minor, Katie M.; Gibbons, Philippa; Rech, Raquel R.; Furrow, Eva

doi:10.1111/jvim.15431

Cited by 4 publications

(5 citation statements)

References 34 publications

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“…However, MutPred2 predicted effects of the variant on protein structure, including gain of an intrinsic disorder and loss of helix, as well as altered ordered interface [17] . Multiple missense variants have previously been reported humans and other species with Xanthinuria Type II, including exon 1 variants, but none are located in close proximity (within 50 amino acids) of the dog variant [22] , [23] , [24] .…”

Section: Discussionmentioning

confidence: 99%

“…The dog is a naturally occurring animal model for both type I and type II hereditary xanthinuria [6] , [7] , [8] , [9] , [10] , [11] , [12] . Other naturally occurring models include cat [36] , [37] , [38] , [39] , cow [26] , [27] , [40] , sheep [41] , and goat [24] . A naturally occurring model could be applied to investigate the correlation between genotype and phenotypic severity.…”

Section: Discussionmentioning

confidence: 99%

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Multiple variants in XDH and MOCOS underlie xanthine urolithiasis in dogs

Tate¹,

Minor²,

Lulich³

et al. 2021

Molecular Genetics and Metabolism Reports

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Hereditary xanthinuria is a rare autosomal recessive disease caused by missense and loss of function variants in the xanthine dehydrogenase ( XDH ) or molybdenum cofactor sulfurase ( MOCOS ) genes. The aim of this study was to uncover variants underlying risk for xanthinuria in dogs. Affected dogs included two Manchester Terriers, three Cavalier King Charles Spaniels, an English Cocker Spaniel, a Dachshund, and a mixed-breed dog. Four putative causal variants were discovered: an XDH c.654G > A splice site variant that results in skipping of exon 8 (mixed-breed dog), a MOCOS c.232G > T splice site variant that results in skipping of exon 2 (Manchester Terriers), a MOCOS p.Leu46Pro missense variant (Dachshund), and a MOCOS p.Ala128Glyfs*30 frameshift variant that results in a premature stop codon (Cavalier King Charles Spaniels and English Cocker Spaniel). The two splice site variants suggest that the regions skipped are critical to the respective enzyme function, though protein misfolding is an alternative theory for loss of function. The MOCOS p.Leu46Pro variant has not been previously reported in human or other animal cases and provides novel data supporting this residue as critical to MOCOS function. All variants were present in the homozygous state in affected dogs, indicating an autosomal recessive mode of inheritance. Allele frequencies of these variants in breed-specific populations ranged from 0 to 0.18. In conclusion, multiple diverse variants appear to be responsible for hereditary xanthinuria in dogs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Multiple variants in XDH and MOCOS underlie xanthine urolithiasis in dogs

Tate¹,

Minor²,

Lulich³

et al. 2021

Molecular Genetics and Metabolism Reports

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“…Causative genetic variants associated with xanthinuria have been identified in humans, dogs, goats and cattle. 5 , 9 , 11 – 29 In cats, the condition is rarely reported, and to date, one exonic candidate variant affecting XDH has been proposed in this species (case 1 of this case series). 30 …”

Section: Introductionmentioning

confidence: 88%

“…Causative genetic variants associated with xanthinuria have been identified in humans, dogs, goats and cattle. 5,9,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] In cats, the condition is rarely reported, and to date, one exonic candidate variant affecting XDH has been proposed in this species (case 1 of this case series). 30 In humans and dogs, purine urolithiasis is effectively managed with a protein-reduced, purine-restricted diet.…”

Section: Introductionmentioning

confidence: 88%

Xanthinuria in a familial group of Munchkin cats and an unrelated domestic shorthair cat

Pritchard,

Haase,

Wall

et al. 2024

Journal of Feline Medicine and Surgery

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Case series summary Four confirmed cases of xanthinuria in cats, and one suspected case based on pedigree analysis, were identified. Clinical presentations varied and included haematuria, pollakiuria, dysuria, and urethral and ureteral obstruction. All cats had upper urinary tract uroliths. Diagnosis was obtained through infrared mass spectrometry of uroliths or urine. Clinical signs commenced at 3–8 months of age and reduced in all cats in the medium to long term after the introduction of a protein-restricted diet. Four cats were castrated males and one was a spayed female. Cases consisted of four Munchkin pedigree cats and one unrelated domestic shorthair cat. All four affected Munchkin pedigree cats were related, with three cases full siblings and the fourth case a half-sibling. No connection to the Munchkin pedigree could be established for the domestic shorthair cat. A candidate causative genetic variant ( XDH p.A681V) proposed for this cat was excluded in the Munchkin family. Relevance and novel information All affected cats presented diagnostic challenges and routine urinalysis was insufficient to obtain a diagnosis. Cases of feline xanthinuria may be underdiagnosed due to situations where uroliths cannot be retrieved for analysis and there is an inability to make a diagnosis using crystal morphology alone on routine urinalysis. Metabolic screening of urine may provide an effective mechanism to confirm xanthinuria in suspected cases where uroliths are inaccessible or absent. In this case series, male cats were more common. Their anatomy may increase the risk of lower urinary tract signs and urethral obstruction developing secondary to xanthine urolithiasis. A protein-restricted diet appears to reduce clinical signs as part of long-term management. Plain language summary Four closely related Munchkin cats and one domestic shorthair cat were found with a suspected genetic disease causing high levels of xanthine in their urine. The case series looks at similarities and differences in their clinical signs, as well as difficulties experienced in obtaining a correct diagnosis. All cats had upper urinary tract stones and required metabolic testing of the stones or urine to diagnose. All cats were young when their clinical signs started and were on a high-protein diet. Four cats were desexed males and one was a desexed female. A genetic variant that may have caused the disease in the domestic shorthair cat was ruled out in the Munchkin family. Cases of high xanthine levels in feline urine may be underdiagnosed as the stones may not be accessed for testing. In this case series, male cats were more common. Their anatomy may increase the risk of lower urinary tract signs. A protein-restricted diet appears to reduce clinical signs as part of long-term management.

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“…While no longer a functional enzyme in humans, hepatic uricase converts uric acid to allantoin in most mammals, which is subsequently excreted by the kidney (Kratzer et al, 2014). Heritable defects associated with xanthinuria and urate crystalluria have been described in humans, dogs, goats, and cattle, and there is evidence that this condition is also heritable in cats (Furman et al, 2015;Gok et al, 2003;Ichida et al, 2012;Miranda et al, 2010;Murgiano et al, 2016;Tate et al, 2016;Vail et al, 2019;Westropp et al, 2017). While relatively rare and predominantly benign in humans, xanthinuria in humans has been subdivided (Ichida et al, 1997(Ichida et al, , 2001.…”

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confidence: 99%

Candidate causative variant for xanthinuria in a Domestic Shorthair cat

Pritchard

Samaha

Mizzi³

et al. 2023

Animal Genetics

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Xanthinuria is a clinically significant form of urolithiasis in cats with poor clinical outcomes and limited treatment options. In humans, xanthinuria has an autosomal recessive mode of inheritance, with variants in xanthine dehydrogenase (XDH) and molybdenum cofactor sulfurase (MOCOS) responsible for cases. While causative genetic variants have not been identified in the domestic cat, a recessive mode of inheritance has been suggested. DNA was extracted from EDTA-stabilised blood obtained from a Domestic Shorthair cat with clinically confirmed xanthinuria.Whole-genome sequencing and variant assessment in XDH and MOCOS identified XDH:c.2042C>T (XDH:p.(A681V)) as a candidate causative variant for xanthinuria in this cat. The variant is located in a highly conserved part of the molybdenum-pterin co-factor domain, responsible for catalysing the hydroxylation of hypoxanthine to xanthine and uric acid. Variants in this domain of XDH have been shown to disrupt enzyme function and to cause xanthinuria in other species. When assessed in the wider cat population, the variant had an allele frequency of 15.8%, with 0.9% of the animals assessed homozygous for the alternative allele. Cats diagnosed with xanthinuria should be tested for this variant to validate its clinical relevance in the wider population.

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Hereditary xanthinuria in a goat

Cited by 4 publications

References 34 publications

Multiple variants in XDH and MOCOS underlie xanthine urolithiasis in dogs

Multiple variants in XDH and MOCOS underlie xanthine urolithiasis in dogs

Xanthinuria in a familial group of Munchkin cats and an unrelated domestic shorthair cat

Candidate causative variant for xanthinuria in a Domestic Shorthair cat

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