In other species: dog

Categories: Renal / urinary system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 603592 (trait) , 613274 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0011346: xanthinuria type II

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2000

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 (OMIA:002445) 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).

History: This disorder was first reported in cattle by Mizoguchi (1997).

Inheritance: Pedigree analysis by Watanabe et al. (2000) revealed autosomal recessive inheritance in Japanese Black cattle. Similar evidence was reported for Tyrolean Grey cattle by Murgiano et al. (2016).

Mapping: By conducting a genome scan on 21 affected offspring and their parents (21 dams and two sires), each genotyped with 200 microsatellites, Watanabe et al. (2000) linkage-mapped this disorder to the "centromeric region of bovine chromosome (BTA) 24". They then FISH-mapped the most likely comparative candidate gene (based on the most likely causative gene in humans), namely Drosophila ma-l orthologue (encoding the putative molybdopterin cofactor sulfurase, which is required for normal activity of both XDH and AO; see Clinical section), to "BTA24q13.1–13.3", which corresponds to the linkage-mapped location of the disorder locus.

Molecular basis: Cloning and sequencing of the bovine gene encoding molybdopterin cofactor sulfurase (MCSU, now called MOCOS) in normal and affected cattle, by Watanabe et al. (2000), revealed the causal mutation to be a 3bp deletion (c.769_771delTAC) of codon 257 (deleting Tyr) in the MOCOS gene (omia.variant:446). Murgiano et al. (2016) discovered a different mutation in the MUCOS gene as the likely cause in Tyrolean Grey cattle: "1 bp deletion in the molybdenum cofactor sulfurase (MOCOS) gene (g.21222030delC; c.1881delG and c.1782delG) [omia.variant:492], located in an 11 Mb region of homozygosity on BTA 24)". Jacinto et al. (2023) reported an affected Brown Swiss animal homozygous for the variant described by Murgiano et al. (2016) (omia.variant:492).

Clinical features: As reported by Watanabe et al. (2000), this disorder is "characterized by elevated xanthine secretion in the urine associated with lethal growth retardation at approximately 6 months of age . . . Affected cattle had expanded renal tubules containing xanthine calculi ranging from 1–3 mm in diameter". A diagnostic feature is the lack of xanthine dehydrogenase (XDH) and aldehyde oxidase (AO).

Prevalence: Watanabe et al. (2000) "confirmed that more than 300 xanthinuria-affected [Japanese Black] cattle have been recorded over the last 20 years and that all parents were descendants of a putative founder sire. Affected male, female, and unknown offspring numbered 177, 148, and 9, respectively." Bhati et al. (2020) reported that two Braunvieh "ancestor bulls born in 1967 and 1974 ... were heterozygous carriers of a single base pair deletion (BTA24:g.21222030delC) [omia.variant:492] in the MOCOS gene that causes xanthinuria in the homozygous state in Tyrolean grey cattle." Jacinto et al. (2023) reported that the prevalence of carriers for omia.variant:492 in 24337 genotyped Brown Swiss cattle was 1.4%.

Breeds: Brown Swiss (Cattle) (VBO_0000166), Japanese Black, Japan (Cattle) (VBO_0004987), Tiroler Grauvieh (Cattle) (VBO_0000408).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: