In other species: taurine cattle

Categories: Renal / urinary system phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 603592 (trait) , 613274 (gene)

Links to MONDO diseases:

• MONDO:0011346: xanthinuria type II

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2021

Cross-species summary: Animals with hereditary xanthinuria (excretion of large amounts of xanthine in the urine) may be asymptomatic, may have subclinical uroliths (xanthine stones), or present with clinical signs of urolithiasis. Urolith formation can be influenced by other biologic and environmental factors such as sex, diet and urine properties. Xanthinuria, type I (OMIA002445) is caused by variation in the XDH gene and xanthinuria, type II (OMIA 001819) is caused by variation in the MOCOS gene. Information relating to xanthinuria without identified causal variants is listed under xanthinuria, generic (OMIA 001283).

Species-specific name: Xanthine urolithiasis; xanthine nephrolithiasis

Inheritance: Tate et al. (2021) conducted pedigree analysis in Manchester Terriers and their findings were consistent with autosomal recessive inheritance.

Molecular basis: Furrow et al. (2016) reported in a conference abstract the identification of three likely disease-causing mutations for xanthine urolithiasis. Affected Cavalier King Charles Spaniels had a mutation resulting in a premature stop codon in the molybdenum cofactor sulfurase gene (MOCOS), affected Toy Manchester Terriers had a splice site mutation in MOCOS, and an affected mixed breed dog had a splice site mutation in the xanthine dehydrogenase (XDH) gene. These findings were included in the publication by Tate et al. (2021). Tate et al. (2021): "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. ...Sanger sequencing of [candidate genes] XDH and MOCOS identified four putative causal variants ... : 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). ... All variants were found in a homozygous state in the affected dogs, consistent with an autosomal recessive mode of inheritance."

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: In affected dogs with MOCOS deficiency excess xanthine builds up in the urine, a product which has a low solubility and readily precipitates out of urine, creating xanthine calculi (Furrow et al., 2016). These calculi act similar to most uroliths, creating partial or complete urethral obstruction, resulting in intermittent or consistent stranguria and dysuria, and may result in secondary renal damage (Furrow et al., 2016). In the dogs investigated by Tate et al. (2021) "age at first diagnosis ranged from 7 weeks to 4 years." IT thanks DVM student Cameron Stuart, who provided the basis of this contribution in May 2023.

Prevalence: The allele frequency of the MOCOS c.232G > T (p.Gly78Cys) variant was 0,13 and 0,10 in 386 Manchester Terriers and 285 English Toy Terriers, respectively. The allele frequency of the MOCOS c.383delC variant was 0.03 and 0 in 109 Cavalier King Charles Spaniels and 42 English Cocker Spaniels, respectively. The MOCOS c.137 T > C variant was absent from a population of 116 Dachshunds. (Tate et al., 2021)

Breeds: Cavalier King Charles Spaniel (Dog) (VBO_0200309), Dachshund (Dog) (VBO_0200406), English Cocker Spaniel (Dog) (VBO_0200486), Manchester Terrier (Dog) (VBO_0200862).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: