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  • Writer's pictureDženita Omerkić Dautovic, MSc & Dr Edin Hamzić

🧬 TPMT Gene & TPMT Deficiency

This first blog post in a series of two blog posts focused on the TPMT is generally composed of three main parts:

  1. An overview of the TPMT gene and the role of the enzyme the TPMT gene encodes.

  2. How TPMT mutations can lead to TPMT deficiency and 

  3. What kind of testing is necessary for detecting TPMT deficiency? 

In the second blog post, that is coming soon, I will be covering the topic of interactions between the TPMT gene and several related drugs, such as thiopurines, azathioprine, and mercaptopurine.

What Is the TPMT Gene?


The TPMT gene was originally described by Remi in 1963 [citation; citation] during the research focused on the process of methylation of thiopurine and thiopyrimidine compounds [citation]. The TPMT in the name is an abbreviation for Thiopurine S-methyltransferase, which is an enzyme that is encoded by the TPMT gene. More about this in the following sections of the post.

Where Is the TPMT Gene Located?

The TPMT gene is located at chromosome 6 and is roughly 34kb long [citation]. Related TPMT pseudogenes have been identified on chromosomes 3, 18, and X [citation].

In the blog, we will use the abbreviation TPMT to denote the enzyme and the TPMT gene to denote the gene.


What Is the TPMT Enzyme?

As mentioned, the TPMT  gene encodes a thiopurine S-methyltransferase (TPMT) enzyme.

The function of the TPMT enzyme is to break down drugs called thiopurines, which are further crucial in treating cancer and other diseases [citation]. 

The TPMT enzyme is one of the critical elements in catalyzing the S-methylation of 6-mercaptopurine (6-MP) and other thiopurine drugs. The catalyzing pathway is involved in processing signals that are further important for mediating the metabolism of cytotoxic agents [citation]. 

As we already mentioned, the TPMT gene encodes the TPMT enzyme that metabolizes thiopurine drugs via S-adenosyl-L-methionine as the S-methyl donor and creates S-adenosyl-L-homocysteine as a byproduct [citation]. Also, this enzyme catalyzes thiopyrimidine compounds [citation]. 

The activity of this enzyme can be detected and measured in human erythrocytes [citation]. TPMT enzyme activity can be used to predict life-threatening myelotoxic events [citation].

Why Is the TPMT Enzyme Important?

TPMT enzyme catalyzes the S-methylation of thiopurine drugs.

There are genetic mutations that can affect levels of TPMT enzyme and its activity and, therefore, are associated with the potential toxicity and therapeutic efficacy of thiopurines.

What Is a Normal TPMT Level?

Sies et al. [citation] have established the normal range of TPMT to be 9.3–17.6 units/ml red blood cells. However, these results can be inconsistent due to recent blood transfusions, certain medications, alcohol, and interlaboratory variation [citation].

What Is TPMT Deficiency? What Causes TPMT Deficiency?

TPMT deficiency refers to a reduced or absent activity of the TPMT enzyme in the body. As we mentioned TPMT is crucial in the metabolism of thiopurine drugs, which are used to treat certain types of cancer, autoimmune diseases, and as immunosuppressants in organ transplantation.

Individuals with TPMT deficiency have a significantly increased risk of developing severe, potentially life-threatening myelosuppression (suppression of the bone marrow's ability to produce blood cells) if they receive standard doses of thiopurine drugs. This is because the deficiency leads to an accumulation of toxic metabolites, which can damage the bone marrow.

TPMT deficiency resulting from genetic mutations in the TPMT gene is characterized by autosomal recessive inheritance, and it is associated with severe hematopoietic toxicity when patients are treated with standard doses of mercaptopurine, azathioprine, or thioguanine [citation]. Deficient TPMT activity is associated with grossly abnormal thiopurine drug metabolism, excess production of cytotoxic metabolites, and profound life-threatening myelotoxicity in patients taking thiopurine drugs [citation].

TPMT deficiency is caused by genetic mutations in the TPMT gene known to reduce enzyme activity. A long list of identified TPMT gene alleles interact in different ways with multiple medications. Table 1 illustrates only the Level 1A (high confidence) interactions between the TPMT gene alleles and two main drugs azathioprine, mercaptopurine.

Table 1: Level 1A gene-drug interactions between the TPMT gene alleles and azathioprine, mercaptopurine.

The TPMT gene alleles


Type of gene-drug interaction


azathioprine, mercaptopurine






Mercaptopurin, azathioprine





What Are Diseases Associated With the Reduced TPMT Enzyme Activity?

Diseases related to reduced function of TPMT enzyme activity include

  1. Thiopurine S-Methyltransferase Deficiency

  2. Autoimmune Hepatitis [citation],

  3. Neutropenia [citation],

  4. Childhood Acute Lymphoblastic Leukemia [citation], and

  5. Veno-Occlusive Disease [citation].


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