NUDT15
Nudix Hydrolase 15 – Key Regulator of Thiopurine Metabolism and Toxicity
Gene Information Card
| Symbol | NUDT15 |
|---|---|
| Full Name | Nudix Hydrolase 15 |
| Gene Type | Protein coding |
| Chromosomal Location | 13q14.2 |
| NCBI Gene ID | 55270 ncbi.nlm.nih.gov/gene/55270 |
| Ensembl ID | ENSG00000165731 |
| UniProt ID | Q9BV35 |
| OMIM ID | 615792 |
| HGNC ID | 23019 |
| Aliases | MTH2, NUDT15D, NUDT15L, hNUDT15 |
Description
NUDT15 encodes a member of the nudix hydrolase superfamily that hydrolyzes nucleoside diphosphates linked to other moieties (e.g., dGTP, dTTP, and thiopurine metabolites). It is a key enzyme in the detoxification of thiopurine drugs (6-mercaptopurine, azathioprine) by converting active thioguanine nucleotides to inactive metabolites. Loss-of-function variants in NUDT15 are strongly associated with thiopurine-induced myelosuppression and leukopenia, particularly in East Asian and Hispanic populations.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Thiopurine-induced myelosuppression | Loss-of-function NUDT15 variants reduce clearance of active thioguanine nucleotides, leading to accumulation and bone marrow toxicity | ClinVar, multiple GWAS studies |
| Acute lymphoblastic leukemia (ALL) treatment toxicity | NUDT15 deficiency increases risk of severe leukopenia during 6-mercaptopurine therapy | ClinVar, COSMIC |
| Inflammatory bowel disease (IBD) thiopurine intolerance | NUDT15 variants predict early thiopurine discontinuation due to leukopenia | ClinVar, NCBI |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Bone marrow | 12.3 | Medium |
| Spleen | 8.7 | Medium |
| Liver | 6.5 | Low |
| Small intestine | 5.2 | Low |
| Whole blood | 4.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| K-562 (leukemia) | 15.2 | High expression |
| HEK 293 (embryonic kidney) | 9.8 | Medium expression |
| HepG2 (liver) | 7.3 | Medium expression |
| HL-60 (promyeloblast) | 6.1 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs116855232 (p.Arg139Cys) | Missense | 9-15% in East Asians; <1% in Europeans | Loss-of-function; reduced thiopurine metabolism |
| rs186364861 (p.Val18Ile) | Missense | 2-5% in East Asians | Loss-of-function; increased toxicity risk |
| rs746071566 (p.Arg139His) | Missense | Rare | Loss-of-function; associated with leukopenia |
| rs147390019 (c.415C>T) | Nonsense | Rare | Loss-of-function; premature stop codon |
Mutation functional classification
Loss of Function (LOF)
Common NUDT15 variants (e.g., p.Arg139Cys, p.Val18Ile) reduce enzymatic activity, leading to accumulation of toxic thioguanine nucleotides and increased risk of myelosuppression.
Gain of Function (GOF)
No gain-of-function variants have been clinically characterized for NUDT15.
Dominant Negative (DN)
No dominant-negative effects have been reported for NUDT15.
View complete mutation data：
Gene Ontology (GO)
| • magnesium ion binding (GO:0000287) | • 8-oxo-7 (GO:0008413) |
| • manganese ion binding (GO:0030145) | • metal ion binding (GO:0046872) |
| • cytoplasm (GO:0005737) | • cytosol (GO:0005829) |
Pathways
• Thiopurine metabolism (Reactome: R-HSA-156581)
• Purine metabolism (KEGG: hsa00230)
• Drug metabolism – other enzymes (KEGG: hsa00983)
Protein Summary
NUDT15 is a 164-amino acid nudix hydrolase that catalyzes the hydrolysis of nucleoside diphosphates, including dGTP, dTTP, and the active thiopurine metabolites (e.g., thioguanine diphosphate). It protects cells from nucleotide pool imbalances and drug toxicity. The protein is predominantly cytoplasmic and expressed in hematopoietic tissues. Loss-of-function mutations reduce thiopurine clearance, leading to severe leukopenia in treated patients.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| NUDT15 Knockout HEK293 Cell Line | EDJ-KQ14516 | Human | 55270 | Details Get a Quote |
| NUDT15 Knockout A-549 Cell Line | EDJ-KQ44790 | Human | 55270 | Details Get a Quote |
| NUDT15 Knockout HCT 116 Cell Line | EDJ-KQ44791 | Human | 55270 | Details Get a Quote |
| NUDT15 Knockout HeLa Cell Line | EDJ-KQ44792 | Human | 55270 | Details Get a Quote |
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