DNMT3A gene

DNA methyltransferase 3 alpha

The DNMT3A gene provides instructions for making an enzyme called DNA methyltransferase 3 alpha. This enzyme is involved in DNA methylation, which is the addition of methyl groups, consisting of one carbon atom and three hydrogen atoms, to DNA molecules. In particular, the enzyme helps add methyl groups to DNA building blocks (nucleotides) called cytosines.

DNA methylation is important in many cellular functions. These include determining whether the instructions in a particular segment of DNA are carried out or suppressed (gene silencing), regulating reactions involving proteins and fats, and controlling the processing of chemicals that relay signals in the nervous system (neurotransmitters). DNA methyltransferase 3 alpha is particularly important for establishing DNA methylation patterns during development before birth. The enzyme also functions in early cells that can give rise to more mature cell types. In early blood cells, called hematopoietic stem cells, the methylation patterns established by DNA methyltransferase 3 alpha promote maturation (differentiation) into different blood cell types.

At least 16 mutations in the DNMT3A gene have been found to cause DNMT3A overgrowth syndrome. This condition is characterized by faster than normal growth before and after birth, a distinctive facial appearance, and intellectual disability.

DNMT3A gene mutations that cause DNMT3A overgrowth syndrome are found in all of the body's cells and lead to a decrease in normal enzyme function. Some of these DNMT3A gene mutations lead to a decrease in normal enzyme function. As a result, there is a reduction in DNA methylation, particularly affecting DNA methylation before birth. It is unclear how other mutations affect protein function. Decreased DNA methylation likely disrupts the normal regulation of important developmental genes, although how these change cause the specific features of DNMT3A overgrowth syndrome is unknown.

At least one DNMT3A gene alteration that causes DNMT3A overgrowth syndrome deletes the entire DNMT3A gene and multiple neighboring genes. While this deletion leads to the signs and symptoms of DNMT3A overgrowth syndrome, it is difficult to determine what role the other missing genes have in contributing to the development of health problems in affected individuals.

Mutations in the DNMT3A gene are associated with a form of blood cancer known as cytogenetically normal acute myeloid leukemia (CN-AML). While large chromosomal abnormalities can be involved in the development of acute myeloid leukemia, about half the cases do not have these abnormalities; these are classified as CN-AML. Up to one-third of people with CN-AML have a mutation in the DNMT3A gene.

The DNMT3A gene mutations involved in CN-AML are called somatic mutations; they are typically found in a small percentage of cells and the mutations are not inherited. Most change single protein building blocks (amino acids) in the DNA methyltransferase 3 alpha enzyme. Studies suggest that these changes make the enzyme less able to fully methylate DNA. It is also thought that the altered pattern of methylation in cells changes the activity of several genes; some genes that are normally silenced may be turned on. Researchers speculate that the altered gene activity prevents hematopoietic stem cells from differentiating normally, which leads to the overproduction of abnormal, immature white blood cells characteristic of acute myeloid leukemia.

Somatic DNMT3A gene mutations are also found relatively frequently in another form of blood cancer called T-cell acute lymphoblastic leukemia. As in cytogenetically normal acute myeloid leukemia (described above), the mutations disrupt the normal pattern of methylation in cells, which blocks differentiation. It is unclear why some people with DNMT3A gene mutations develop acute myeloid leukemia and others develop acute lymphoblastic leukemia.

Cytogenetic Location: 2p23.3, which is the short (p) arm of chromosome 2 at position 23.3

Molecular Location: base pairs 25,232,961 to 25,342,590 on chromosome 2 (Homo sapiens Annotation Release 108, GRCh38.p7) (NCBI)

Cytogenetic Location: 2p23.3, which is the short (p) arm of chromosome 2 at position 23.3
  • DNA (cytosine-5-)-methyltransferase 3 alpha
  • DNA (cytosine-5)-methyltransferase 3A
  • DNA cytosine methyltransferase 3A2
  • DNA MTase HsaIIIA
  • DNM3A_HUMAN
  • DNMT3A2
  • M.HsaIIIA