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A comparison of molecular and enzyme-based assays for the detection of thiopurine methyltransferase mutations

Lookup NU author(s): Dr Sally Coulthard, Dr Christopher Howell, Lynne Minto, Dr Peter Middleton, Professor Graham Jackson, Dr Janet McLelland, Dr Michael Reid, Professor Andrew Pearson, Dr Andrew Hall


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S-Methylation by thiopurine methyltransferase (TPMT) is an important route of metabolism for the thiopurine drugs. About one in 300 individuals are homozygous for a TPMT mutation associated with very low enzyme activity and severe myelosuppression if treated with standard doses of drug. To validate the use of molecular genetic techniques for the detection of TPMT deficiency, we have determined red blood cell TPMT activity in 240 adult blood donors and 55 normal children. Genotype was determined by restriction fragment length analysis of polymerase chain reaction products in a cohort of 79 of the blood donors and five cases of azathioprine-induced myelosupression, and this confirmed a close relationship between genotype and phenotype. In 17 of the 24 cases in which mutations were found, DNA was also available from remission bone marrow. In one of these cases, DNA from the remission marrow sample indicated the presence of a non-mutated allele that had not been seen in the blast DNA sample obtained at presentation. These results indicate that polymerase chain reaction-based assays give reliable and robust results for the detection of TPMT deficiency, but that caution should be exercised in relying exclusively on DNA obtained from lymphoblasts in childhood leukaemia.

Publication metadata

Author(s): Coulthard, S., Rabello, C., Robson, J., Howell, C., Minto, L., Middleton, P., Gandhi, M., Jackson, G., McLelland, J., O'Brien, H., Smith, S., Reid, M., Pearson, A., Hall, A.

Publication type: Article

Publication status: Published

Journal: British Journal of Haematology

Year: 2000

Volume: 110

Issue: 3

Pages: 599-604

Print publication date: 01/01/2000

ISSN (print): 0007-1048

ISSN (electronic): 1365-2141


DOI: 10.1046/j.1365-2141.2000.02218.x

PubMed id: 10997970


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