Nudix hydrolase 15 is a protein that in humans is encoded by the NUDT15 gene.[1]
Function
This gene encodes an enzyme that belongs to the Nudix hydrolase superfamily. Members of this superfamily catalyze the hydrolysis of nucleoside diphosphates, including substrates like 8-oxo-dGTP, which are a result of oxidative damage, and can induce base mispairing during DNA replication, causing transversions. The encoded enzyme is a negative regulator of thiopurine activation and toxicity. Mutations in this gene result in poor metabolism of thiopurines, and are associated with thiopurine-induced early leukopenia. Multiple pseudogenes of this gene have been identified.
NUDT15 germline variants (e.g., a missense SNP:rs116855232, inducing R139C) have been linked to clinical usage of thiopurines (e.g., mercaptopurine) in acute lymphoblastic leukemia[2][3] as well as inflammatory bowel diseases to avoid thiopurine-induced leukopenia.[4][5] These variants also exhibit ethnicity-specific (e.g.,variant allele of rs116855232 is high is East Asians and Hispanics but low in Caucasians and Africans). Rare functional variants even singletons in this gene have also been identified to be related to thiopurine-induced myelotoxicity,[6] suggesting the whole gene screening should be taken to determine the initial dosage using of thiopurine.
↑Moriyama T, Nishii R, Perez-Andreu V, Yang W, Klussmann FA, Zhao X, et al. (April 2016). "NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity". Nature Genetics. 48 (4): 367–73. doi:10.1038/ng.3508. PMID26878724.
↑Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, et al. (April 2015). "Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia". Journal of Clinical Oncology. 33 (11): 1235–42. doi:10.1200/JCO.2014.59.4671. PMID25624441.
↑Yang SK, Hong M, Baek J, Choi H, Zhao W, Jung Y, et al. (September 2014). "A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia". Nature Genetics. 46 (9): 1017–20. doi:10.1038/ng.3060. PMID25108385.
↑Yin D, Xia X, Zhang J, Zhang S, Liao F, Zhang G, et al. (February 2017). "Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose". Oncotarget. 8 (8): 13575–13585. doi:10.18632/oncotarget.14594. PMID28088792.
↑Moriyama, T; Yang, YL; Nishii, R; Ariffin, H; Liu, C; Lin, TN; Yang, W; Lin, DT; Yu, CH; Kham, S; Pui, CH; Evans, WE; Jeha, S; Relling, MV; Yeoh, AE; Yang, JJ (28 June 2017). "Novel variants in NUDT15 and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry". Blood. doi:10.1182/blood-2017-05-782383. PMID28659275.
Hori M, Satou K, Harashima H, Kamiya H (May 2010). "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. 48 (9): 1197–201. doi:10.1016/j.freeradbiomed.2010.02.002. PMID20144704.
Tanaka Y, Kato M, Hasegawa D, Urayama KY, Nakadate H, Kondoh K, et al. (October 2015). "Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia". British Journal of Haematology. 171 (1): 109–15. doi:10.1111/bjh.13518. PMID26033531.
