Xanthinuria type II is a rare hereditary disorder caused by mutations in the MOCOS gene, leading to dual deficiency of xanthine dehydrogenase and aldehyde oxidase. To establish a robust animal model for this condition, we generated Mocos knock-in (KI) rats carrying the Arg419Ter nonsense mutation identified in Japanese patients. Homozygous KI rats exhibited severe growth retardation, anemia, and reduced survival, with all individuals dying by 14 weeks of age. Biochemical analyses revealed elevated levels of hypoxanthine and xanthine, along with decreased uric acid in both serum and urine, confirming xanthinuria. Homozygous KI rats also showed increased blood creatinine (CRE) and urea nitrogen (UN), and decreased urinary CRE and UN, indicating renal dysfunction. Histopathological examination showed obstructive nephropathy characterized by tubular atrophy, crystal deposition, and inflammation. Compared to existing mouse models, Mocos KI rats demonstrated extended lifespan, enabling more detailed investigation of disease mechanisms. This rat model provides a valuable tool for studying the pathogenesis of xanthinuria type II and exploring potential therapeutic strategies.

Uric acid is an important metabolic end-product in the human body, and metabolic abnormalities involving uric acid are receiving increasing attention. This study involved clinical assessment and genetic testing of a 40-year-old male patient who presented with the main complaint of hypouricemia for 7 years. In addition to hypouricemia, the patient showed low urinary uric acid levels, low uric acid excretion rate, and nephrolithiasis. His younger brother also showed extremely low serum uric acid levels. Trio-whole-genome sequencing (trio-WGS) showed that the proband and his younger brother had a compound heterozygous molybdenum cofactor sulfurase (MOCOS) genotype with the pathogenic variant c.1272T>A (p.Cys424Ter) and the likely pathogenic variant c.1418C>T (p.Ser473Leu). The final diagnosis was Xanthinuria type II. A review of the literature for cases of Xanthinuria type II revealed reports describing 25 patients from 17 families. All 25 patients showed very low serum uric acid levels, eight showed urinary tract stones, and three reported joint or limb pain. Truncation pathogenic or likely pathogenic variants of the MOCOS gene accounted for nearly half of the cases, and p.Arg419Ter and p.Thr349Ile were the two most frequent variants. The p.Cys424Ter variant reported in this study is a new pathogenic site that has not been reported previously. Sustained low serum uric acid levels may indicate monogenic uric acid metabolism disorders, and these patients should undergo genetic testing. In patients diagnosed with xanthinuria type II caused by MOCOS gene variants, the use of purine drugs should be prohibited to avoid serious adverse events. Given the severe defects in the MOCOS gene-deficient mouse model, additional research is needed to clarify the clinical profile of Xanthinuria type II and the other roles of MOCOS in metabolic pathways.

A recessive form of MOCOS-associated xanthinuria type II is described in Tyrolean grey cattle. A similar case was identified in a 5-month-old Brown Swiss calf with hoof overgrowth, rough coat, urine sediment, and pneumonia. To characterize the disease phenotype, to evaluate its genetic etiology, and to determine the prevalence of the deleterious allele in the Brown Swiss population. An affected calf, its parents, and 65 441 Swiss dairy cattle. The affected animal was clinically examined and necropsied. Microarray genotyping was used to determine the genotypes and to assess the frequency of the MOCOS allele in a Brown Swiss control cohort. Ultrasonography revealed hyperechoic renal pyramids with multifocal distal shadowing and echogenic sediment in the urinary bladder. Necropsy revealed suppurative bronchopneumonia and urolithiasis. Histology revealed numerous nephroliths with multifocal chronic lymphohistiocytic interstitial infiltrates, fibrosis, tubular degeneration, chronic multifocal glomerulonephritis with sclerosis, and bilateral hydronephrosis. Dysplastic changes were observed in the corium of the claw and the cornea. Genetic testing identified the homozygous presence of a known MOCOS frameshift variant in the case. Both parents were heterozygous and the prevalence of carriers in genotyped Brown Swiss cattle was 1.4% (342/24337). The findings were consistent with the diagnosis of a recessive renal syndrome similar to xanthinuria type II described in Tyrolean grey cattle. The prevalence of the deleterious MOCOS allele is low in the Brown Swiss breed. However, mating of carriers should be avoided to prevent further losses.

Xanthinuria type II is a rare autosomal purine disorder. This recessive defect of purine metabolism remains an under-recognized disorder. Mice with targeted disruption of the molybdenum cofactor sulfurase (Mocos) gene were generated to enable an integrated understanding of purine disorders and evaluate pathophysiologic functions of this gene which is found in a large number of pathways and is known to be associated with autism. Mocos-deficient mice die with 4 weeks of age due to renal failure of distinct obstructive nephropathy with xanthinuria, xanthine deposits, cystic tubular dilation, Tamm-Horsfall (uromodulin) protein (THP) deposits, tubular cell necrosis with neutrophils, and occasionally hydronephrosis with urolithiasis. Obstructive nephropathy is associated with moderate interstitial inflammatory and fibrotic responses, anemia, reduced detoxification systems, and important alterations of the metabolism of purines, amino acids, and phospholipids. Conversely, heterozygous mice expressing reduced MOCOS protein are healthy with no apparent pathology. Mocos-deficient mice develop a lethal obstructive nephropathy associated with profound metabolic changes. Studying MOCOS functions may provide important clues about the underlying pathogenesis of xanthinuria and other diseases requiring early diagnosis.