Multiple variants in XDH and MOCOS underlie xanthine urolithiasis in dogs

Abstract

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.

Trends in urolith composition and factors associated with different urolith types in dogs from the Republic of Ireland and Northern Ireland between 2010 and 2020

“…Among purine uroliths, those that contain urate are encountered in dogs with either congenital portosystemic shunts, or in dogs with a SLC2A9 mutation error in metabolism resulting in hyperuricosuria (Bannasch et al ., 2008; Bartges & Callens, 2015; Karmi et al ., 2010). Xanthine uroliths are reported in dogs undergoing treatment with allopurinol as well as in dogs with a xanthine dehydrogenase mutation (xanthinuria type I) or A molybdenum cofactor sulfurase mutation (xanthinuria type II) (Tate et al ., 2021). Therefore, the fact that purine uroliths are mainly retrieved from dogs with genetic metabolic defects explains their high prevalence in a younger population as reported in this cohort.…”

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

“…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.…”

“…4,8,9 Xanthinuria can also be subclinical, further complicating diagnosis. 5,[10][11][12][13] In the absence of xanthine dehydrogenase (XDH) inhibitory therapy, xanthinuria is typically hereditary, with an autosomal recessive mode of inheritance, and results from variants affecting the function of XDH (type I xanthinuria) or its cofactor molybdenum cofactor sulfurase (MOCOS) (type II xanthinuria). Causative genetic variants associated with xanthinuria have been identified in humans, dogs, goats and cattle.…”

Candidate causative variant for xanthinuria in a Domestic Shorthair cat

“…Variants in MOCOS have been associated with xanthinuria in various species (Murgiano et al, 2016; Peretz et al, 2021; Sedda et al, 2021; Tate et al, 2021). Except the missense variant in exon 7 of the feline MOCOS gene, all remaining exonic variants had no effect on the amino acid sequence.…”

“…The observed allele frequency and high number of cats homozygous for the alternative alleles for the two variants in the 5′UTR make it unlikely that they are responsible for the observed phenotype. Variants in MOCOS have been associated with xanthinuria in various species (Murgiano et al, 2016;Peretz et al, 2021;Sedda et al, 2021;Tate et al, 2021). Except the missense variant in exon 7 of the feline MOCOS gene, all remaining exonic variants had no effect on the amino acid sequence.…”