Ataxia-Telangiectasia

Kevin D. Brown, Ph.D.

Ataxia-Telangiectasia (a-TACK-see-ah tel-AN-gee-eck-tay-sha) is a rare genetic disorder. It is estimated that between 1 in 40,000 and 1 in 100,000 babies born in the U.S. are afflicted with A-T. Nevertheless, this disorder is ultimately fatal for children suffering from this disease and heartbreaking for A-T families.

Signs of the disorder usually first become noticeable between 1-4 years of age. During their toddler years affected children have problems with balance control (termed ataxia), as shown by unsteady walking. Often times, prominent blood vessels most commonly seen on the whites of the eyes or on the skin of the face are observed (termed telangiectasia). The ataxia is due to the death of a specific type of cell in the brain called Purkinje (per-KIN-gee) cells, and the loss of these cells is a gradual but continuous process (termed progressive neuronal degeneration). Speech problems often occur, as well as a gradual loss of power and other coordination problems. Ultimately and generally during adolescence, A-T patients are permanently wheelchair bound.

A-T patients also have a compromised immune system and, because of this, often contract recurrent respiratory tract infections. Additionally, A-T patients have an extremely high likelihood of developing cancer, primarily leukemia or lymphoma. A-T patients show a handful of other maladies, such as premature aging, sterility, diabetes, and growth defects. Owing primarily to either cancer or infection, A-T claims the life of afflicted patients, most in their teens or twenties.

Much of the early work on understanding the nature of the A-T disorder came from work conducted on cells taken from A-T patients (termed A-T cells). It was observed that the DNA in A-T cells was extremely susceptible to undergoing rearrangements. Also, it was found that A-T cells are very sensitive to the effects of gamma-radiation, the type of radiation used in cancer therapy. Exposure of cells to gamma-radiation results in DNA damage, and it is this property that is used to kill cancer cells. Later it was found by Dr. Michael Kastan and colleagues at Johns Hopkins University School of Medicine that A-T cells were defective in initiating signals that normally occur in a cell exposed to gamma-radiation. This work on A-T cells laid a solid foundation of research indicating that the A-T disorder was due to, at least in part, the inability to respond in an appropriate manner to DNA damage. As a result of this defect, the cells in A-T patients accumulate harmful alterations in their DNA.

Because of the way that A-T is inherited (termed autosomal recessive inheritance), scientists were able to deduce that A-T was due to the loss of a single gene. More specifically, A-T patients fail to make a particular protein due to an alteration (termed mutation) in a single gene. After a long and arduous process, the gene responsible for A-T was discovered in 1995 by Dr. Yossi Shiloh at Tel Aviv University in Israel. His team termed this gene (and the protein that it produces) ATM (for A-T, mutated).

By analyzing the structure of the protein encoded by the ATM gene, the Shiloh group was able to conclude that it was likely that the ATM protein functions as a protein kinase. Protein kinases are a very large and diverse family of proteins responsible for adding small phosphate groups onto proteins. Such events (termed phosphorylation) act primarily as molecular switching devices, turning on and off a wide variety of cellular events and processes.

While discovery of the A-T gene did not directly result in a cure, it did set the stage for a flood of research into the cellular basis of A-T. This was because researchers now had a particular protein to focus their experiments upon. The development of antibodies that recognize the ATM protein allowed our group, as well as others, to determine that ATM was primarily located in the nucleus of cells, although a small portion of the ATM is present in the cytoplasm of the cell. This finding made sense because we knew that ATM was important in maintaining DNA stability, and the cell's nucleus is where the DNA resides. Other groups confirmed that ATM is indeed a protein kinase and that it phosphorylates a number of other molecules involved in response to DNA damage inflicted by gamma-radiation.

At this point in time, we have obtained sufficient information to solve many pieces of the A-T disorder puzzle. For example, the reason why A-T patients have such a high likelihood of developing cancer is fairly clear. As I have outlined above, A-T cells do not respond appropriately to DNA damaging events such as gamma-radiation. Because damage to our DNA occurs on a daily basis, this means that A-T cells accumulate mutations at a much higher rate than normal cells. Since cancer development is almost invariably driven by the accumulation of such mutations in the DNA, we feel confident that the leukemias and lymphomas often seen in A-T patients are due to the inefficient maintenance of DNA integrity inherent to A-T cells.

So too, the immune deficiencies observed in A-T patients may be due to faulty DNA damage response. Cells responsible for mounting the immune response follows the invasion of the body by foreign organisms (such as bacteria and viruses) are termed lymphocytes. When lymphocytes begin the process of responding to foreign organisms, they rearrange their DNA in a process called recombination. ATM is important in assuring that the DNA integrity is maintained; thus, it makes sense that in ATM-deficient lymphocytes that have undergone recombination there exists a higher likelihood of poorly recombined (damaged) DNA . As a result of this, lymphocytes containing DNA that has undergone faulty recombination cannot properly participate in the immune response and, overall, the capabilities of the immune system are diminished. Because recombination is an important event in the development of sperm and eggs, it is likely that similar effects lead to infertility in A-T patients.

Recently, we have begun to understand the reason for the diabetes and poor growth often associated with the A-T disorder. For example, when insulin binds to the outside of the cell, it stimulates uptake of sugar (glucose) from the blood stream. This is why patients who do not produce enough insulin (diabetics) have high glucose levels in their blood. It was uncovered that ATM plays a key role in signaling events that stimulate a cell to take up more glucose. This is likely not due to the function of the ATM residing within the cell's nucleus; rather it is seemingly a function of the small amount of ATM present in the cell's cytoplasm. Similarly, our group at LSUHSC has found that ATM may be important in signaling events that occur in response to growth factors and this may explain some of the growth abnormalities seen in A-T patients.

The reason why A-T patients display neuronal degeneration has remained puzzling. It seems unlikely that poor maintenance of DNA integrity is to blame since Purkinje cells do not continue to grow once they are formed before or shortly after birth. In a recent study conducted by Dr. Carrolee Barlow at the Salk Institute and our lab at LSUHSC, we found that nerve cells from ATM-deficient mice do not develop correctly. Further, we found that after normal nerve cells develop ATM levels in these cells undergo a dramatic decline. These experiments told us that ATM is important in nerve cell development and is likely to not play a major role in nerve cell functions after their development. Thus, we think that neuronal degeneration is a natural outcome of brain development in the absence of ATM and not due to post-developmental occurrences.

While the hard work of my lab and colleagues around the globe has resulted in many advances toward understanding the reasons for the A-T disorder, much has yet to be learned. For example, we do not know what turns on ATM activity after DNA damage. Additionally, scientists continue to discover new molecules that are targets for ATM phosphorylation and the consequences of these events. This is important work because it increases our knowledge of the functions of ATM. A major effort in our lab is directed toward understanding the types of DNA damage that activate ATM. This work will tell us the breadth of the involvement of ATM in responding to DNA damage. By increasing our knowledge of ATM functions, we hope, as a long-term goal, to design better treatment strategies for this currently incurable disorder. One especially intriguing possibility is the use of gene therapy to replace defective ATM genes with a good copy of the gene in the cells of A-T patients.

Another area of active investigation is understanding the role that ATM plays in cancer development in people not afflicted with A-T. It has been found that mutations in ATM occur in several types of leukemias and it is thought that this plays a key role in the development of this type of tumor. Additionally, studies on A-T families have shown that A-T carriers (people with one bad and one good copy of the ATM gene) are at increased risk of developing breast cancer. We, as well as other labs, are currently trying to understand the reasons for this increased risk and are working to determine potential role for ATM in the development of breast cancer.

Finally, I have mentioned that A-T cells are very sensitive to the effects of gamma-radiation. Gamma-radiation is commonly used as a treatment for many types of cancer; however, often times tumors can be resistant to the killing effects of radiation rendering this treatment of limited use. It is possible that drugs could be designed and administered to cancer patients that would block the function of ATM and hence render tumors more susceptible to gamma-radiation therapy.

While we have made many advances in the recent years toward understanding the A-T disorder and the function of the ATM protein, much has yet to be learned. However, as we acquire greater knowledge and develop better tools to attack this issue, we are seemingly only limited by the bounds of human imagination and ingenuity.

How to Learn More
For more information on the A-T disorder, available treatments, medical and family support please contact the A-T Children's Project at www.atcp.org .


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