Candidate causative variant for xanthinuria in a Domestic Shorthair cat

Abstract

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.

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

“…Whole-genome sequencing results for this case have previously been reported and revealed homozygosity for a candidate causal variant for xanthinuria affecting XDH (p.A681V). 30 …”

“…At 1073 days after original presentation, the cat was clinically well, had a stable body weight, body condition score of 4–5/9 and had IRIS stage 3 chronic kidney disease (creatinine 292 µmol/l, RI 68–167; urea 15.6 mmol/l, RI 4.3–11.7). The genetic variant XDH p.A681V 30 was excluded by PCR for this case.…”

“…Three years later, the cat remained clinically well, with creatinine of 200 µmol/l (RI 80–200), urea 17.5 mmol/l (RI 5.0–15.0), SDMA 16 µg/dl (RI 0–14) and USG 1.021. The genetic variant XDH p.A681V 30 was excluded by PCR for this case.…”

“…Renal parameters and USG remained static, and episodes of haematuria reduced in frequency over 3.5 years of follow-up. The genetic variant XDH p.A681V 30 was excluded by PCR for this case.…”

“… 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 …”