Ataxia Telangiectasia Mutated Kinase
The ATM protein was identified as the product of the gene that is mutated (lost or inactivated) in the human genetic disorder ataxia-telangiectasia (A-T). A-T belongs to a group of human diseases that are collectively known as genomic instability syndromes , each of which results from a defective response to a specific DNA lesion. A-T is characterized by cerebellar degeneration, which leads to severe, progressive neuromotor dysfunction, immunodeficiency, genomic instability, thymic and gonadal atrophy, a striking predisposition to lymphoreticular malignancies and extreme sensitivity to ionizing radiation and DSB-inducing agents. This devastating human disorder typically combines most of the hallmarks of a defective DNA-damage response, clearly pointing to the DSB as the DNA lesion that elicits this defect. Indeed, cultured cells from A-T patients show a broad defect in responding to DSBs that span almost all of the known branches of this response. The striking clinical and cellular phenotype that is caused by ATM loss clearly places this protein at a top position in the DSB-response cascade.
From Clinical Evidence
Ataxia Telangiectasia is an autosomal recessive disorder (1:40,000- 1:300,000);
0,35-1% heterozigotes in the general populaton.
The disorder is characterized by defects in a number of a distinct organ systems:
- progressive cerebellar ataxia
- telangiectasias in skin and conjunctiva of the eye
- chromosomal instability
- radiation sensitivity
- increased incidence of malignancies, primarly of limphoid origin:
- 40% Non-hodgkin;s limphoma,
- 25% Leukaemia,
- 25% Assorted solid tumours,
- 10% Hodgkin’s limphoma.
To Genetic Characterization
What is the normal function of the ATM gene?
The ATM gene provides instructions for making a protein that is located primarily in the nucleus of cells, where it helps control the rate at which cells grow and divide. This protein also plays an important role in the normal development and activity of several body systems, including the nervous system and the immune system. Additionally, the ATM protein assists cells in recognizing damaged or broken DNA strands. DNA can be damaged by agents such as toxic chemicals or radiation. Breaks in DNA strands also occur naturally when chromosomes exchange genetic material during cell division. The ATM protein coordinates DNA repair by activating enzymes that fix the broken strands. Efficient repair of damaged DNA strands helps maintain the stability of the cell’s genetic information.
Because of its central role in cell division and DNA repair, the ATM protein is of great interest in cancer research.
How are changes in the ATM gene related to health conditions?
- caused by mutations in the ATM gene
Researchers have identified several hundred mutations in the ATM gene that cause ataxia-telangiectasia. People with this disorder have mutations in both copies of the ATM gene in each cell. Most of these mutations disrupt protein production, resulting in an abnormally small, nonfunctional version of the ATM protein. Cells without any functional ATM protein are hypersensitive to radiation and do not respond normally to DNA damage. Instead of activating DNA repair, the defective ATM protein allows mutations to accumulate in other genes, which may cause cells to grow and divide in an uncontrolled way. This kind of unregulated cell growth can lead to the formation of cancerous tumors. In addition, ATM mutations can allow cells to die inappropriately, particularly affecting cells in a part of the brain involved in coordinating movements (the cerebellum). This loss of brain cells causes the movement problems characteristic of ataxia-telangiectasia.
- associated with the ATM gene
Researchers have found that having a mutation in one copy of the ATM gene in each cell (particularly in people who have at least one family member with ataxia-telangiectasia) is associated with an increased risk of developing breast cancer. About 1 percent of the United States population carries one mutated copy of the ATM gene in each cell. These genetic changes prevent
many of the body’s cells from correctly repairing damaged DNA.
People who have only one copy of the ATM gene in each cell due to a gene deletion are also at an increased risk of developing breast cancer. Cells that are missing one copy of the ATM gene produce half the normal amount of ATM protein. A shortage of this protein prevents efficient repair of DNA damage, leading to the accumulation of mutations in other genes. This buildup of mutations is likely to allow cancerous tumors to develop.
- increased risk from variations of the ATM gene
Research suggests that people who carry one mutated copy of the ATM gene in each cell may have an increased risk of developing several other types of cancer. In particular, some studies have shown that cancers of the stomach, bladder, pancreas, lung, and ovaries occur more frequently in ATM mutation carriers than in people who do not carry these mutations.
The results of similar studies, however, have been conflicting. Additional research is needed to clarify which other types of cancer, if any, are associated with ATM mutations.
Where is the ATM gene located?
Cytogenetic Location: 11q22.3
Molecular Location on chromosome 11 Link al gene