Thiopurine-induced toxicity is associated with dysfunction variant of the human molybdenum cofactor sulfurase gene (xanthinuria type II)
Language English Country United States Media print-electronic
Document type Case Reports, Journal Article, Research Support, Non-U.S. Gov't
PubMed
29935280
DOI
10.1016/j.taap.2018.06.015
PII: S0041-008X(18)30281-3
Knihovny.cz E-resources
- Keywords
- Azathioprine, Human molybdenum cofactor sulfurase, Hypouricemia, Thiopurine-induced toxicity, Xanthinuria,
- MeSH
- Aldehyde Oxidase deficiency genetics MeSH
- Adult MeSH
- Uric Acid blood MeSH
- Humans MeSH
- Mercaptopurine adverse effects analogs & derivatives metabolism MeSH
- Methyltransferases genetics MeSH
- Polymorphism, Genetic genetics MeSH
- Purine-Pyrimidine Metabolism, Inborn Errors genetics MeSH
- Sulfurtransferases genetics MeSH
- Xanthine urine MeSH
- Xanthine Dehydrogenase deficiency genetics MeSH
- Xanthine Oxidase genetics MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Aldehyde Oxidase MeSH
- AOX1 protein, human MeSH Browser
- azathiopurine MeSH Browser
- Uric Acid MeSH
- Mercaptopurine MeSH
- Methyltransferases MeSH
- MOCOS protein, human MeSH Browser
- Sulfurtransferases MeSH
- TPMT protein, human MeSH Browser
- Xanthine MeSH
- Xanthine Dehydrogenase MeSH
- Xanthine Oxidase MeSH
BACKGROUND: The aim of our study was to identify the genetic background of thiopurine-induced toxicity in a patient with a wild-type thiopurine methyltransferase genotype and activity. A 38-year-old Caucasian woman presented with cutaneous necrotizing vasculitis pancytopenia one month after starting azathioprine therapy. METHODS: During a routine biochemical follow-up of the patient, undetectable serum uric acid (<10 μl) was observed. A high performance liquid chromatography analysis of urinary purines revealed increased levels of xanthine (137 mmol/mol creatinine). The suspected diagnosis of hereditary xanthinuria, a rare autosomal recessive disorder of the last two steps of purine metabolism, was confirmed by sequence analysis. RESULTS: An analysis of XDH/XO and AOX1 revealed common polymorphisms, while analysis of the MOCOS gene identified a rare homozygous variant c.362C > T. Dysfunction of this variant was confirmed by significantly decreased xanthine dehydrogenase/oxidase activity in the patient's plasma (<2% of control mean activity). CONCLUSIONS: We present a biochemical, enzymatic, and molecular genetic case study suggesting an important association between a hitherto undescribed dysfunction variant in the MOCOS gene and thiopurine-induced toxicity. The identified variant c.362C > T results in slower thiopurine metabolism caused by inhibition of 6-mercaptopurine oxidation (catabolism) to 6-thioxanthine and 6-thiouric acid, which increases the formation of the nucleotide 6-thioguanine, which is toxic. This is the first clinical case to identify the crucial role of the MOCOS gene in thiopurine intolerance and confirm the impact of genetic variability of purine enzymes on different therapeutic outcomes in patients undergoing thiopurine treatment.
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