NUDT15
Nudix 水解酶 15是一种在人类中由 NUDT15 基因编码的蛋白质[5]。
功能
此基因编码的是一种属于Nudix 水解酶超家族的酶。该超家族的成员能催化核苷酸的水解，包括像 8-oxo-dGTP 这样的基质，这些基质是氧化损伤的产物，它们在DNA复制期间会诱导碱基错配且颠换突变。编码的酶是硫嘌呤活化和毒性的负调节器。此基因突变会使硫嘌呤代谢不良，并与硫嘌呤产生的早期白血球减少症有关。已识别出此基因的多个假基因。
NUDT15 种系变异（例如，一种错义 SNP:rs116855232，诱导 R139C）已经与硫嘌呤（例如，mercaptopurine、6-巯嘌呤（6-MP）、硫唑嘌呤（AZA，azathioprine））在临床上治疗急性淋巴性白血病[6][7]及发炎性肠道疾病时，宜减量或停用以避免硫嘌呤造成的白血球低下[8][9]。这些变异具有种族特异性（例如，rs116855232 的变异等位基因在东亚人和西班牙裔人中较高，但在高加索人和非洲人较低）。此基因上的罕见功能变异，甚至是单一点位变异，也已识别出与硫嘌呤造成的骨髓抑制有关[10] ，并建议在决定硫嘌呤的初始剂量时，应进行全基因筛检。
临床重要性
硫嘌呤类药物常用于治疗自体免疫疾病、防止器官移植排斥和血液病的药物。然而，其活性代谢物会经由硫嘌呤甲基转移酶 (Thiopurine methyltransferase，TPMT) 及 Nudix 水解酶 15（此水解酶由 NUDT15 基因编码）两种酵素，进行代谢及灭活作用。根据研究，TPMT 基因表现为弱代谢型者，发生于欧美及非裔族群之机率较高（约 0.3%），于东亚裔族群之发生机率较为罕见；NUDT15基因表现为弱代谢型者，发生于东亚裔族群之机率约为 2%（具风险之基因变异频率约为9.8%），于欧美族群中较为罕见（<1%）[11]。
根据印度以研究，以硫唑嘌呤治疗发炎性肠道疾病时，带有 NDUT15 弱代谢型者发生白血球低下的发生率为 53.8%（7/13），带有 TPMT 弱代谢型者发生白血球低下的发生率为 20.0%（1/5），而未带这两类弱代谢型者发生白血球低下的发生率为 24.5%（25/102）。NUDT15 而非 TPMT 基因变异与白血球低下的发生率有关。但虽有弱代谢型基因者，仍有 40% 以上没有副作用，到没带弱代谢型基因者，也有 20% 的机会可能有副作用。总结，有此弱代谢型基因者未必发生副作用，没此弱代谢型基因者也可能发生副作用，临床使用上，仍需特别小心与注意[12]。
参考文献
- ^ 1.0 1.1 1.2 GRCh38: Ensembl release 89: ENSG00000136159 - Ensembl, May 2017
- ^ 2.0 2.1 2.2 GRCm38: Ensembl release 89: ENSMUSG00000033405 - Ensembl, May 2017
- ^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Entrez Gene: Nudix hydrolase 15.
- ^ Moriyama T, Nishii R, Perez-Andreu V, Yang W, Klussmann FA, Zhao X, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nature Genetics. April 2016, 48 (4): 367–73. PMC 5029084
. PMID 26878724. doi:10.1038/ng.3508.
- ^ Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. Journal of Clinical Oncology. April 2015, 33 (11): 1235–42. PMC 4375304 . PMID 25624441. doi:10.1200/JCO.2014.59.4671.
- ^ Yang SK, Hong M, Baek J, Choi H, Zhao W, Jung Y, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nature Genetics. September 2014, 46 (9): 1017–20. PMC 4999337 . PMID 25108385. doi:10.1038/ng.3060.
- ^ Yin D, Xia X, Zhang J, Zhang S, Liao F, Zhang G, et al. Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose. Oncotarget. February 2017, 8 (8): 13575–13585. PMC 5355121 . PMID 28088792. doi:10.18632/oncotarget.14594.
- ^ Moriyama T, Yang YL, Nishii R, Ariffin H, Liu C, Lin TN, et al. Novel variants in NUDT15 and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry. Blood. September 2017, 130 (10): 1209–1212. PMC 5606007 . PMID 28659275. doi:10.1182/blood-2017-05-782383.
- ^ 含azathioprine成分藥品安全資訊風險溝通表. [2023-12-31] （中文（台湾））.
- ^ TPMT and NUDT15 polymorphisms in thiopurine induced leucopenia in inflammatory bowel disease: a prospective study from India.. BMC Gastroenterol: 327. [2023-12-31]. doi:10.1186/s12876-021-01900-8.
延伸阅读
- Yu Y, Cai JP, Tu B, Wu L, Zhao Y, Liu X, et al. Proliferating cell nuclear antigen is protected from degradation by forming a complex with MutT Homolog2. The Journal of Biological Chemistry. July 2009, 284 (29): 19310–20. PMC 2740556 . PMID 19419956. doi:10.1074/jbc.M109.015289 .
- Hori M, Satou K, Harashima H, Kamiya H. Suppression of mutagenesis by 8-hydroxy-2'-deoxyguanosine 5'-triphosphate (7,8-dihydro-8-oxo-2'-deoxyguanosine 5'-triphosphate) by human MTH1, MTH2, and NUDT5. Free Radical Biology & Medicine. May 2010, 48 (9): 1197–201. PMID 20144704. doi:10.1016/j.freeradbiomed.2010.02.002. hdl:2115/43020 .
- Yang SK, Hong M, Baek J, Choi H, Zhao W, Jung Y, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nature Genetics. September 2014, 46 (9): 1017–20. PMC 4999337 . PMID 25108385. doi:10.1038/ng.3060.
- Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. Journal of Clinical Oncology. April 2015, 33 (11): 1235–42. PMC 4375304 . PMID 25624441. doi:10.1200/JCO.2014.59.4671.
- Tanaka Y, Kato M, Hasegawa D, Urayama KY, Nakadate H, Kondoh K, et al. Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia. British Journal of Haematology. October 2015, 171 (1): 109–15. PMID 26033531. doi:10.1111/bjh.13518 .
- Kakuta Y, Naito T, Onodera M, Kuroha M, Kimura T, Shiga H, et al. NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD. The Pharmacogenomics Journal. June 2016, 16 (3): 280–5. PMID 26076924. doi:10.1038/tpj.2015.43 .
- Carter M, Jemth AS, Hagenkort A, Page BD, Gustafsson R, Griese JJ, et al. Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2. Nature Communications. August 2015, 6: 7871. Bibcode:2015NatCo...6.7871C. PMC 4532830 . PMID 26238318. doi:10.1038/ncomms8871.
- Chiengthong K, Ittiwut C, Muensri S, Sophonphan J, Sosothikul D, Seksan P, et al. NUDT15 c.415C>T increases risk of 6-mercaptopurine induced myelosuppression during maintenance therapy in children with acute lymphoblastic leukemia. Haematologica. January 2016, 101 (1): e24–6. PMC 4697903 . PMID 26405151. doi:10.3324/haematol.2015.134775.
- Liang DC, Yang CP, Liu HC, Jaing TH, Chen SH, Hung IJ, et al. NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia. The Pharmacogenomics Journal. November 2016, 16 (6): 536–539. PMID 26503813. S2CID 13955512. doi:10.1038/tpj.2015.75.
外部连节
NUDT15引用了美国国家医学图书馆提供的资料，这些资料属于公共领域。