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.

遗传性黄嘌呤尿症是一种罕见的常染色体隐性遗传疾病，由黄嘌呤脱氢酶 ( XDH ) 或钼辅因子硫酸酶 ( MOCOS ) 基因错义和功能缺失变异引起。这项研究的目的是揭示狗黄嘌呤尿症潜在风险的变异。受影响的狗包括两只曼彻斯特梗犬、三只骑士查尔斯王小猎犬、一只英国可卡犬、一只腊肠犬和一只混种狗。发现了四种假定的因果变异：导致外显子 8 跳跃的XDH c.654G > A 剪接位点变异（混种犬）、导致外显子 2 跳跃的MOCOS c.232G > T 剪接位点变异（曼彻斯特）梗犬）、 MOCOS p.Leu46Pro 错义变体（腊肠犬）和导致过早终止密码子的MOCOS p.Ala128Glyfs*30 移码变体（骑士查理王小猎犬和英国可卡犬）。这两个剪接位点变异表明，跳过的区域对于各自的酶功能至关重要，尽管蛋白质错误折叠是功能丧失的另一种理论。 MOCOS p.Leu46Pro 变体此前尚未在人类或其他动物病例中报道过，并提供了新的数据支持该残留物对 MOCOS 功能至关重要。所有变异在受影响的狗中均以纯合状态存在，表明常染色体隐性遗传模式。这些变异在特定品种群体中的等位基因频率范围为 0 至 0.18。总之，多种不同的变异似乎是导致狗遗传性黄嘌呤尿症的原因。