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Thiopurin S-Methyltransferase Mutations - TPMT

Toxicitity after Thiopurin Therapie

Clinical Features

The TPMT gene codes for the enzyme Thiopurine S-Methyltransferase, which catalyses S-methylation and thus the inactivation of thiopurines. Thiopurines (Azathioprine, 6-Mercaptopurine and 6-Thioguanine) are used as cytostatic and immunosuppressive agents in the treatment of Crohn's Disease, childhood leukaemia, chronic hepatitis and organ transplantation.

TPMT inactivity, the deciding factor in thiopurine tolerance and/or toxicity, is subject to genetic polymorphisms in the TPMT gene. About 10% of Caucasians have a reduction in TPMT activity of 75%, while approximately every 300th person shows no TPMT activity whatsoever (TPMT*3A).

Reduced TPMT activity leads to an increased incidence of side-effects after the administration of a standard dose of thiopurine. Tumor patients-especially children-who carry the genetic mutations TPMT*2, TPMT*3B or TPMT*3C in the TPMT gene have an increased risk of suffering severe, life-threatening side-effects (neutropenia) while undergoing azathioprine, mercaptopurine or thioguanine therapy.

Genetic Information

The TPMT gene is located on chromosome 6p22.3. Taken together, the TPMT gene mutations described below are responsible for 97% of reduced TPMT activity and are detected by analysis:

• A mutation in nucleotide 238 (substitution of G by C), resulting in an exchange of amino acids alanine and proline (allele TPMT*2), causes enzyme activity to decrease by a factor of about 100.
• A mutation in nucleotide 460 (substitution of G by A), resulting in an exchange of amino acids alanine and threonine (allele TPMT*3B), causes enzyme activity to decrease by a factor of about 9.
• A mutation in nucleotide 719 (substitution of A by G), resulting in an exchange of amino acids tyrosine and cysteine (allele TPMT*3C), causes enzyme activity to decrease by a factor of about 1.4. When these last two mutations (TPMP*3B and TPMT*3C) occur together, enzyme activity sinks by a factor of about 200 (allele TPMT*3A).

Prevalence

TPMT*3A: approximately 1 : 300
TPMT*2 / TPMT*3B / TPMT*3C: approximately 1 : 10

Diagnostic