TEL AVIV, ISRAEL The discovery of a gene for a rare inherited childhood neurological disorder called ataxia telangiectasia (A-T) also has significant implications for cancer researchers, reported an international team of researchers.AT is an inherited neuromotor deteriorating disease that strikes somewhere between 1 in 40,000 to 1 in 100,000 people. It's usually first noticed in toddlers with an unsteady gait; it kills by young adulthood. Individuals with two copies of the ATM gene have the fatal disorder. People with one copy of the ATM gene don't get the disease, but are carriers and appear to have a predisposition to certain cancers that is three to four times higher than that of the general population. Female carriers of the AT gene have a significantly increased risk for breast cancer.
The researchers have cloned a single gene called ATM, that when mutated causes AT. The researchers also report that this ATM gene is similar to genes involved in signal transduction, DNA repair and cell cycle control. For families at risk for AT, the discovery could lead to diagnostic tests in the short term and the effective treatments in the long term. On a broader level, the research team believes they have also have identified a common genetic marker indicating predisposition to certain cancers. The discovery may also help identify individuals who are sensitive to radiation.
Researchers had been working under the assumption that several different genes were involved in AT. However, the sequence of the ATM gene and studies of its alterations in patients suggest that this gene alone is responsible for all A-T cases and for the various manifestations of the disease, according to Yosef Shiloh, Ph.D, associate professor of human genetics at Tel Aviv's Sackler School of Medicine and senior author of the study.
"By finding the gene for A-T, we not only gain tremendous knowledge about a devastating childhood neurological disorder, but also acquire some insights into what makes certain people predisposed to cancer" noted Zach W. Hall, Ph.D., director of the NIH's National Institute of Neurological Disorders and Stroke, one of the sponsors of this study. "This unusual finding provides a clue that will help us understand the link between cell division and cell death and reinforces the notion that no disease is too rare to merit full scientific investigation."
When biochemical studies of tissues from children with the disorder failed to give a clue to the cause of A-T, scientists began looking directly at DNA, searching for a gene that encoded a causative protein. Using powerful tools developed at the Human Genome Project, the scientists applied the strategy of positional cloning. First, genetic analysis of A-T families pinpointed the location of the ATM gene on chromosome 11. Then Shiloh and his coworkers developed more closely spaced genetic markers across this region on chromosome 11, allowing a consortium of research teams to narrow down the interval where the A-T gene resides. Next, the researchers isolated the particular region of DNA and began sorting through the 10 to 20 gene candidates located in that region. The second candidate gene tested was found to contain mutations that inactivate its protein product in A-T patients.
The normal copy of the A-T gene encodes a protein similar to an enzyme called phosphatidylinositol 3kinase (PI 3-kinase), which is involved in the transfer of signals that control the rate of cell proliferation in response to environmental stimuli. A group of similar enzymes has been found in various organisms to be involved in immune responses and the control of cell growth and division. Other studies have shown that PI 3-kinase is required for the prevention of apoptosis, or programmed cell death. This may explain why A-T patients experience increased nerve cell death. The defective PI 3-kinase may also block other cell regulatory functions, including glucose transport, which may explain the insulin-resistant diabetes in some A-T patients.
The ATM protein appears to resemble the products of two yeast genes--ESR1 (MEC1) and rad3--both of which are required for the correct control of the cell cycle. These proteins serve as checkpoints to ensure that each step of the cell cycle is carried out only after a previous step has been completed, and that the DNA is undamaged. DNA damage, like that inflicted by ionizing radiation, is a signal to halt the cell cycle and allow a repair mechanism to complete its work before continuing. When rad3 is defective, yeast cells become more sensitive to irradiation. This may explain the increased vulnerability of A-T patients to ionizing radiation. noted Shiloh.
The ability to identify A-T carriers will give researchers an important tool to help study the apparent increase in cancer risk among such carriers, said noted researcher Francis Collins, M.D., Ph.D., director of the National Center for Human Genome Research and a collaborator in the study. "Concerns about increased radiation sensitivity in carriers can now be studied. If a direct link exists, identifying A-T carriers might allow those individuals to be particularly vigilant for signs of cancer, since early diagnosis of cancer is often critical for successful management. But at the present time, it would be premature for this information to be used to alter screening recommendations for mammography or other diagnostic procedures. Because the ATM gene contains several different mutations that result in A-T, finding all of them, and determining which DNA alterations contribute to the disease and which are harmless variations, will be necessary before a reliable test can be developed."
The research, reported in Science, 6/23/95, v. 268, pp 1749-1753, represents a collaboration among some 30 scientists around the world. More information is available from CancerNet via the NIH gopher, at: "gopher.nih.gov". Look for CancerNet under "Health and Clinical Information."