Institute of Rheumatology, Prague, Czech Republic; Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, General University Hospital in Prague, Prague, Czech Republic.
Institute of Rheumatology, Prague, Czech Republic; Department of Rheumatology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
Toxicol Appl Pharmacol. 2018 Aug 15;353:102-108. doi: 10.1016/j.taap.2018.06.015. Epub 2018 Jun 20.
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.
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.
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).
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.
本研究旨在鉴定一位巯嘌呤甲基转移酶野生型且有酶活性的患者发生巯嘌呤诱导毒性的遗传背景。一位 38 岁的白人女性在开始使用硫唑嘌呤治疗一个月后出现皮肤坏死性血管炎伴全血细胞减少。
在对患者进行常规生化随访期间，发现其血清尿酸（<10μl）无法检出。尿嘌呤的高效液相色谱分析显示黄嘌呤水平升高（137mmol/mol 肌酐）。遗传性黄嘌呤尿症的可疑诊断，一种罕见的嘌呤代谢最后两步的常染色体隐性遗传病，通过序列分析得到确认。
XDH/XO 和 AOX1 分析显示常见的多态性，而 MOCOS 基因分析发现了一种罕见的纯合变体 c.362C>T。患者血浆中黄嘌呤脱氢酶/氧化酶活性显著降低（<对照平均活性的 2%），证实了该变体功能障碍。
我们提出了一个生化、酶学和分子遗传学的病例研究，表明 MOCOS 基因中一个迄今未知的功能障碍变体与巯嘌呤诱导的毒性之间存在重要关联。鉴定出的变体 c.362C>T 导致 6-巯基嘌呤氧化（分解代谢）为 6-硫代黄嘌呤和 6-硫代尿酸的能力下降，从而抑制 6-巯基嘌呤代谢，增加毒性核苷酸 6-硫代鸟嘌呤的形成。这是首例确定 MOCOS 基因在巯嘌呤不耐受中的关键作用并证实嘌呤酶遗传变异性对接受巯嘌呤治疗的患者不同治疗结果的影响的临床病例。
