DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for xanthinuria type II — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleXanthinuria type II maps to a 3-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for xanthinuria type ii is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
xanthine dehydrogenase (XDH) — XDH is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet bctdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2E1Q · 2.6 Å · ligand BICARBONATE ION (BCT). Experimental structure, not a prediction.
What the evidence adds up to
Xanthinuria type II is a rare autosomal recessive disorder caused by a deletion mutation at tyrosine 257 in the molybdopterin cofactor sulfurase gene (MCSU, also called MOCOS), which leads to loss of xanthine dehydrogenase and aldehyde oxidase activity while preserving sulfite oxidase activity. In a cohort of 13 Israeli families and two isolated German cases studied between 1997 and 2013, 7 out of 20 affected individuals (35%) presented with xanthinuria-related symptoms of varied severity. Among the 10 distinct variants identified in that cohort, two were in the MOCOS gene: c.1046C>T (p.(Thr349Ileu)) and c.1771C>T (p.(Pro591Ser)). Heterologous expression studies showed that the p.Thr349Ileu variant in the NifS-like domain affects protein stability and cysteine desulfurase activity, while the p.Pro591Ser variant in the C-terminal domain affects molybdenum cofactor binding.
A 2024 case report describes a 23-year-old male with type II xanthinuria confirmed by genetic studies who reached end-stage renal disease and successfully underwent kidney transplant surgery, currently living with a functioning graft. In a 1997 case, a four-year-old dachshund bitch with congenital xanthinuria presented with terminal chronic renal failure and bilateral nephrolithiasis composed of 100% xanthine; two of her siblings showed higher urine xanthine concentrations than a control dog.
A 2025 study identified an ultra-rare MOCS2 variant (rs776441627) in five Roma patients from four unrelated families, aged 3 to 43 years, who had hypouricemia, accumulation of xanthine and hypoxanthine, deficiency of xanthine oxidase activity, and only asymptomatic or mild clinical course. This variant, which has an allele frequency of 3.6% in a Roma population control group, causes a mild form of molybdenum cofactor deficiency (xanthinuria type III) with fully penetrant biochemical phenotype but minimal neurological symptoms, in contrast to the severe early-onset neurological disease typical of most MOCS2 variants. Functional studies showed significantly decreased molybdopterin synthase complex formation and activity.
What is still missing: larger prospective natural history studies to establish the true proportion of patients who progress to end-stage renal disease, systematic screening of at-risk populations (such as Roma communities) to determine prevalence, and clinical trials of any intervention to prevent stone formation or preserve kidney function. No drug treatment is mentioned in any of these abstracts.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Biological Chemistry · 2000 · 62 citations · open access
Deletion Mutation in Drosophila ma-l Homologous, Putative Molybdopterin Cofactor Sulfurase Gene Is Associated with Bovine Xanthinuria Type II
AbstractDefective xanthine dehydrogenase (XDH) activity in humans results in xanthinuria and xanthine calculus accumulation in kidneys. Bovine xanthinuria was demonstrated in a local herd and characterized as xanthinuria type II, similar to the Drosophila ma-l mutations, which lose activities of molybdoenzymes, XDH, and aldehyde oxidase, although sulfite oxidase activity is preserved. Linkage analysis located the disease locus at the centromeric region of bovine chromosome 24, where a ma-l homologous, putative molybdopterin cofactor sulfurase gene (MCSU) has been physically mapped. We found that a deletion mutation at tyrosine 257 in MCSU is tightly associated with bovine xanthinuria type II.
Mutational analysis of the xanthine dehydrogenase gene in a Turkish family with autosomal recessive classical xanthinuria
AbstractBACKGROUND: Classical xanthinuria is classified into two categories: type I, deficient only in xanthine dehydrogenase (XDH) activity; and type II, deficient in both XDH and aldehyde oxidase. Both types present mainly with renal stones and lead to renal failure in some cases. We studied the molecular basis of xanthinuria in a Turkish family with two affected siblings. METHODS: We examined two brothers aged 1 and 14 years who presented with histories of passing several urinary stones. We measured their serum and urine levels of uric acid and oxypurine, chemically analysed their stones and performed allopurinol loading tests to diagnose the type of xanthinuria. In addition, we studied the coding regions of the XDH gene in family members. RESULTS: In the siblings, serum uric acid was undetectable and serum oxypurine was elevated. Laboratory studies showed that the stones that they passed were composed of xanthine, and both were diagnosed as having classical xanthinuria. The allopurinol loading tests indicated their xanthinuria to be type I. Within the entire coding region of the XDH gene, an A to T base change at nucleotide position 2164 was identified in the siblings, indicating a nonsense substitution from AAG (Lys) to TAG (Tyr) at codon 722. Concerning this novel nonsense mutation, restriction fragment length polymorphism (RFLP) analysis showed that the brothers were both homozygous, while the parents were heterozygous, and this confirmed the autosomal recessive inheritance of the XDH gene mutation. CONCLUSIONS: In a Turkish family, we identified a novel point mutation in the XDH gene responsible for classical type I xanthinuria. That both parents had a history of passing renal stones in spite of being heterozygous for that mutation may indicate that individuals with a heterozygous nonsense XDH mutation are more susceptible to nephrolithiasis than healthy individuals. This raises the point that individuals with a heterozygous XDH mutation may also present with renal stones.
Journal of Small Animal Practice · 1997 · 29 citations
Bilateral xanthine nephrolithiasis in a dog
AbstractXanthinuria is an uncommon metabolic disorder clinically manifested as urolithiasis. There are two forms of the disease, congenital and iatrogenic. The former was diagnosed in a four-year-old dachshund bitch. The patient was presented with signs of terminal chronic renal failure. Urine was bacteriologically sterile with massive amorphous crystalluria. Bilateral nephrolithiasis was diagnosed at necropsy. The kidneys were shrunken with marked atrophy of the renal cortex and medulla. Infrared spectrometry revealed that the stones comprised 100 per cent xanthine. Later, two of the patient's siblings were examined for urine xanthine content; both showed higher concentrations of xanthine than a control dog. The described case is compared with seven known published cases of congenital xanthinuria.
Variations in Allopurinol Metabolism by Xanthinuric Subjects
Abstract1. The metabolism of allopurinol was studied in a newly discovered patient with xanthinuria. 2. No oxipurinol was detectable in the urine during allopurinol administration, in direct contrast to the results in a patient previously studied by one of us. 3. Other equally discrepant effects of allopurinol on urinary purine and pyrimidine excretion in these two cases are compared with those in the three other recorded cases.
New England Journal of Medicine · 1970 · 16 citations
Allopurinol and Xanthine Nephropathy
AbstractTreatment with allopurinol results in an induced xanthinuria. Allopurinol inhibits xanthine oxidase, the enzyme that catalyzes oxidation of hypoxanthine to xanthine and of xanthine to uric acid,1 and in so doing reduces serum and urinary uric acid values while causing slight elevations of hypoxanthine and xanthine in serum and marked increases of these oxypurines in the urine.2 Thus, allopurinol produces a pharmacologic phenocopy of hereditary xanthinuria, an autosomal recessive condition characterized by gross deficiency of xanthine oxidase in tissues.3 The levels of xanthine found in serum and urine of patients treated with allopurinol are similar to those found in hereditary . . .
Classical Xanthinuria in Nine Israeli Families and Two Isolated Cases from Germany: Molecular, Biochemical and Population Genetics Aspects
AbstractClassical xanthinuria is a rare autosomal recessive metabolic disorder caused by variants in the XDH (type I) or MOCOS (type II) genes. Thirteen Israeli kindred (five Jewish and eight Arab) and two isolated cases from Germany were studied between the years 1997 and 2013. Four and a branch of a fifth of these families were previously described. Here, we reported the demographic, clinical, molecular and biochemical characterizations of the remaining cases. Seven out of 20 affected individuals (35%) presented with xanthinuria-related symptoms of varied severity. Among the 10 distinct variants identified, six were novel: c.449G>T (p.(Cys150Phe)), c.1434G>A (p.(Trp478*)), c.1871C>G (p.(Ser624*)) and c.913del (p.(Leu305fs*1)) in the XDH gene and c.1046C>T (p.(Thr349Ileu)) and c.1771C>T (p.(Pro591Ser)) in the MOCOS gene. Heterologous protein expression studies revealed that the p.Cys150Phe variant within the Fe/S-I cluster-binding site impairs XDH biogenesis, the p.Thr349Ileu variant in the NifS-like domain of MOCOS affects protein stability and cysteine desulfurase activity, while the p.Pro591Ser and a previously described p.Arg776Cys variant in the C-terminal domain affect Molybdenum cofactor binding. Based on the results of haplotype analyses and historical genealogy findings, the potential dispersion of the identified variants is discussed. As far as we are aware, this is the largest cohort of xanthinuria cases described so far, substantially expanding the repertoire of pathogenic variants, characterizing structurally and functionally essential amino acid residues in the XDH and MOCOS proteins and addressing the population genetic aspects of classical xanthinuria.
European Journal of Pediatrics · 2025 · 1 citations · open access
A prevalent MOCS2 variant in the Roma population is associated with a novel mild form of molybdenum cofactor deficiency
AbstractXanthinurias are rare inherited disorders of purine metabolism. Xanthinuria type III is caused by molybdenum cofactor deficiency (MoCD) due to pathogenic variants in MOCS1, MOCS2, MOCS3, or GEPH genes. Here, we described five Roma patients from four unrelated families with hypouricemia, accumulation of xanthine/hypoxanthine, deficiency of xanthine oxidase activity, variable age of diagnosis, and only asymptomatic or mild clinical course. Whole exome sequencing was performed on all probands, aged 3 to 43 years, due to lack of genetic confirmation for xanthinuria types I and II. The causality of the putative pathogenic variant was confirmed by analysis of sulfite and related metabolites and in vitro functional characterization of metal-binding pterin (MPT) synthesis and protein complex formation. Considering the rarity of the condition and recessive inheritance, 34 candidate variants were identified after filtering out allele frequency threshold in non-Finnish Europeans. An ultra-rare MOCS2 variant rs776441627 in two overlapping reading frames (c.244A > T (NM_176806.4; p.Ile82Phe) = c.57A > T (NM_004531.5; p.Leu19Phe)) segregated with the disease in all five patients (four homozygotes, one compound heterozygote). The variant has an allele frequency of 3.6% in a Roma population control group. Functional characterization revealed the significantly decreased MPT synthesis activity and confirmed the causality of rs776441627 in MoCD. CONCLUSION: The rs776441627 is a functional variant for MoCD with a mild to asymptomatic clinical phenotype and fully penetrant biochemical phenotype. Hypouricemia should be considered in the differential diagnostic algorithm of pediatric and adult patients with neurological symptoms, and MOCS2 should be considered in gene panels for xanthinuria screening. WHAT IS KNOWN: • Xanthinuria type III is caused by molybdenum cofactor deficiency (MoCD) due to pathogenic variants in MOCS1, MOCS2, MOCS3, or GEPH genes. • The majority of patients with xanthinuria III present with classical early-onset MoCD due to autosomal recessive variants in the MOCS1 gene, manifesting severe progressive neurological complications during the first postnatal days. • To date, approximately 40 patients with MoCD due to pathogenic MOCS2 variants have been reported; most were diagnosed during the neonatal period with intractable seizures and feeding disorders. WHAT IS NEW: • A novel ultra-rare variant, rs776441627, located in two overlapping reading frames of the MOCS2, was identified in five Roma patients presenting a mild to asymptomatic clinical MoCD phenotype and a fully penetrant biochemical phenotype. • Functional studies of p.Ile82Phe (small MOCS2A subunit) and p.Leu19Phe (large MOCS2B subunit) demonstrate a strong reduction in molydopterin synthase complex formation and activity, consistent with the changes in biomarkers of MoCD observed in affected individuals. • The rs776441627 variant shows significantly elevated frequency among the Roma population, highlighting the importance of considering ethnic background in the differential diagnosis of MoCD. • Hypouricemia may provide an initial, generally available biochemical key marker indicator of molybdenum cofactor deficiency.
Indian Journal of Nephrology · 2024 · 0 citations · open access
Successful Kidney Transplantation in a Young Male with Type 2 Xanthinuria
AbstractType-II Xanthanuria is an genetic disorder associated with diminished serum uric acid levels. Patients with xanthanuria has absence of xanthine oxidase or xanthine dehydrogenase activity, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. Deficiency of these enzyme leads to elevated levels of xanthine in urine which further leads to precipitation of xanthine in urine which further helps to formation of renal stones and ultimately leads to chronic kidney disease and end stage renal disease. We report a 23 years old male, who reached ESRD due to Type 2 xanthinuria, which was confirmed by genetic studies, who later successfully underwent renal transplant surgery and currently having normal life with functioning graft.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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