ArticleProceedings of the National Academy of Sciences of the United States of America1995
A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1995. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
67 citing papers in PubMed, 1 synthesis or guideline pooled it, 307 citations in OpenAlex.
- NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity.Nature genetics · 2016Pooled it
- Trial
- Article
- Pharmacogenomics Applied to Acute Leukemias: Identifying Clinically Relevant Genetic Variants.Biomedicines · 2025Review
- The NUDIX hydrolase NUDT5 regulates thiopurine metabolism and cytotoxicity.The Journal of clinical investigation · 2025Article
- Exploring the Pharmacogenetic Landscape: Identification of Clinically Relevant Genotypes by a Nation-Wide Medical Testing Laboratory in Romania.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Clinical Actionability of the NUDT15 *4 (p.R139H) Allele and Its Association With Hispanic Ethnicity.Clinical pharmacology and therapeutics · 2025Article
- Review
- Informing Implementation Strategies for Pharmacogenomics in Cancer: Development of Survey Tools for Healthcare Professionals and Consumers.Clinical and translational science · 2025Article
- Exploring Water-Soluble South AfricanCurrent issues in molecular biology · 2024Article
- Additive effects of TPMT and NUDT15 on thiopurine toxicity in children with acute lymphoblastic leukemia across multiethnic populations.Journal of the National Cancer Institute · 2024Article
- Population-Specific Distribution ofTherapeutics and clinical risk management · 2023Article
- A bioinformatics approach to the identification of novel deleterious mutations of human TPMT through validated screening and molecular dynamics.Scientific reports · 2022Article
- TPMT and NUDT15 Genotyping Recommendations: A Joint Consensus Recommendation of the Association for Molecular Pathology, Clinical Pharmacogenetics Implementation Consortium, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, European Society for Pharmacogenomics and Personalized Therapy, and Pharmacogenomics Knowledgebase.The Journal of molecular diagnostics : JMD · 2022Review
- Ontogeny of Pediatric Pharmacogenetics: Celebrating the Past and Vision for the Future.The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG · 2022Article
- Association Between Genetic Polymorphisms of Metabolic Enzymes and Azathioprine-Induced Myelosuppression in 1,419 Chinese Patients: A Retrospective Study.Frontiers in pharmacology · 2021Article
- Determination of NUDT15 variants by targeted sequencing can identify compound heterozygosity in pediatric acute lymphoblastic leukemia patients.Scientific reports · 2020Article
- Role of Genetic Variations in the Hepatic Handling of Drugs.International journal of molecular sciences · 2020 · on this mapReview
- Massively parallel variant characterization identifiesProceedings of the National Academy of Sciences of the United States of America · 2020Article
- Implementation of Pharmacogenetics to Individualize Treatment Regimens for Children with Acute Lymphoblastic Leukemia.Pharmacogenomics and personalized medicine · 2020Review
7 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Thiopurine S-methyltransferase (TPMT; S-adenosyl-L-methionine:thiopurine S-methyltransferase, EC 2.1.1.67) activity exhibits genetic polymorphism, with approximately 0.33% of Caucasians and African-Americans inheriting TPMT deficiency as an autosomal recessive trait. To determine the molecular genetic basis for this polymorphism, we cloned the TPMT cDNA from a TPMT-deficient patient who had developed severe hematopoietic toxicity during mercaptopurine therapy. Northern blot analysis of RNA isolated from leukocytes of the deficient patient demonstrated the presence of TPMT mRNAs of comparable size to that in subjects with high TPMT activity. Sequencing of the mutant TPMT cDNA revealed a single point mutation (G238-->C), leading to an amino acid substitution at codon 80 (Ala80-->Pro). When assessed in a yeast heterologous expression system, this mutation led to a 100-fold reduction in TPMT catalytic activity relative to the wild-type cDNA, despite a comparable level of mRNA expression. A mutation-specific PCR amplification method was developed and used to detect the G238-->C mutation in genomic DNA of the propositus and her mother. This inactivating mutation in the human TPMT gene provides insights into the genetic basis for this inherited polymorphism in drug metabolism.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.