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15 April 1997 | Volume 126 Issue 8 | Pages 608-614
Background: Thiopurine S-methyltransferase (TPM) catalyzes the S-methylation (that is, inactivation) of mercaptopurine, azathioprine, and thioguanine and exhibits genetic polymorphism. About 10% of patients have intermediate TPM activity because of heterozygosity, and about 1 in 300 inherit TPM deficiency as an autosomal recessive trait. If they receive standard doses of thiopurine medications (for example, 75 mg/m2 body surface area per day), TPM-deficient patients accumulate excessive thioguanine nucleotides in hematopoietic tissues, which leads to severe and possibly fatal myelosuppression.
Objective: To elucidate the genetic basis and develop molecular methods for the diagnosis of TPM deficiency and heterozygosity.
Design: Diagnostic test evaluation.
Setting: Research hospital.
Patients: The TPM phenotype was determined in 282 unrelated white persons, and TPM genotype was determined in all persons who had intermediate TPM activity (heterozygotes) and a randomly selected, equal number of persons who had high activity. In addition, genotype was determined in 6 TPM-deficient patients.
Measurements: Polymerase chain reaction (PCR) assays were developed to detect the G238C transversion in TPM*2 and the G460A and A719G transitions in TPM*3 alleles. Radiochemical assay was used to measure TPM activity. Mutations of TPM were identified in genomic DNA, and the concordance of TPM genotype and phenotype was determined.
Results: 21 patients who had a heterozygous phenotype were identified (7.4% of sample [95% CI, 4.7% to 11.2%]). TPM*3A was the most prevalent mutant allele (18 of 21 mutant alleles in heterozygotes; 85%); TPM*2 and TPM*3C were more rare (about 5% each). All 6 patients who had TPM deficiency had two mutant alleles, 20 of 21 patients (95% [CI, 76% to 99.9%]) who had intermediate TPM activity had one mutant allele, and 21 of 21 patients (100% [CI, 83% to 100%]) who had high activity had no known TPM mutation. Detection of TPM mutations in genomic DNA by PCR coincided perfectly with genotypes detected by complementary DNA sequencing.
Conclusions: The major inactivating mutations at the human TPM locus have been identified and can be reliably detected by PCR-based methods, which show an excellent concordance between genotype and phenotype. The detection of TPM mutations provides a molecular diagnostic method for prospectively identifying TPM-deficient and heterozygous patients.
Author and Article Information
For author affiliations and current author addresses, see end of text.
ARTICLE
Molecular Diagnosis of Thiopurine S-Methyltransferase Deficiency: Genetic Basis for Azathioprine and Mercaptopurine Intolerance
Acknowledgments: The authors thank Amy E. Atkinson, Linh Nguyen, and YaQin Chu for technical assistance; Sheri Ring, Margaret Edwards, and Lisa Walters for collecting blood samples; Dr. Howard McLeod for contributions to the phenotyping studies; Dr. Clayton W. Naeve of the SJCRH Biotechnology Resource Center; Drs. Mark Roberts, Denis R. Miller, Nora R. Rogers, D.J. Murry, and Gaston K. Rivera for their clinical acumen in the recognition and treatment of TPM-deficient patients; Dr. J. Boyett for guidance in the statistical analyses; and the patients and family members who participated in the study.
Grant Support: In part by grant R37 CA36401, Leukemia Program Project grant CA20180, and Cancer Center CORE grant CA21765 from the National Institutes of Health; by a Center of Excellence grant from the State of Tennessee; and by American Lebanese Syrian Associated Charities.
Requests for Reprints: William E. Evans, PharmD, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794.
Current Author Addresses: Mr. Yates and Drs. Krynetski, Fessing, Tai, Relling, and Evans: Pharmaceutical Sciences, Thomas Tower, Room 1052, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105.
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