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Gene Found for Fatal Childhood Disease, Ataxia-Telangiectasia

June 1995

Scientists have isolated the gene and identified mutations that cause the childhood disease ataxia-telangiectasia (A-T), a rare hereditary neurological disorder. Discovery of the gene paves the way for more accurate diagnosis in the short term and the potential for effective treatments in the long term. With this discovery, the investigators believe they also have identified a common genetic marker that indicates predisposition to certain cancers, and may help identify individuals who are sensitive to radiation.

The study results, funded in part by the NIH's National Institute of Neurological Disorders and Stroke (NINDS) and the A-T Children's Project, are reported in the June 23, 1995 issue of Science.

Yosef Shiloh, Ph.D. led an international team of investigators, based primarily in laboratories at Tel Aviv University in Israel and at the National Human Genome Research Institute (NHGRI), to find the gene believed to be the cause of A-T. According to Shiloh, associate professor of human genetics at Tel Aviv's Sackler School of Medicine and senior author on the report, the new findings explain how mutations in the A-T gene, called ATM for "mutated in A-T," can cause the variety of neurological, immunological and other health problems experienced by children with A-T. Because the normal ATM gene appears to play a role in regulating cell division, scientists hope the discovery will also shed light on more common types of cell-cycle disorders, especially cancers.

A-T is a recessive disorder, meaning a child must inherit two altered copies of the ATM gene - one from each parent - to develop the disorder. Scientists have known for some time that people who do not have the disease, but who carry one altered copy of the ATM gene, have about a fourfold increase in cancer compared with the general population. In particular, women who carry A-T mutations have up to a fivefold increased risk of breast cancer compared with control groups. An estimated 1 percent of the general population - about 2.5 million people in the United States - are carriers for A-T mutations. Concerns have been raised that this group of individuals is also more sensitive to radiation exposure.

"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," said 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.

t that several different genes caused this fatal neurological disease. According to Shiloh, "A-T is a complex disorder with many diverse symptoms. In addition, biochemical studies indicated that the disease might be determined by four different genes," he said. "But the sequence of the ATM gene and our studies of its alterations in patients suggest that this gene alone is responsible for the various manifestations of the disease."

Biochemical studies of tissues from children with the disorder failed to give a clue to the cause of A-T, presumably a malfunctioning protein linked to the different features of the disease. So scientists began looking directly at DNA, searching for a gene that encoded such a protein. Using powerful gene-finding tools derived from the Human Genome Project (HGP), 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 them to narrow down the interval where the A-T gene resides. Shiloh and his collaborators isolated that region of DNA and sorted through the 10-20 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 3-kinase (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.

Shiloh and colleagues report that the ATM protein resembles 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.

A-T affects between 1 in 40,000 and 1 in 200,000 individuals worldwide. Some 500 children in the United States have A-T, although it is suspected that many more are undiagnosed. The first sign of the disease is a neurological defect (ataxia) stemming from loss of specific cells in part of the brain. The disease is first noticed in toddlers by the appearance of unsteady gait, involuntary movements, slurred speech, and difficulty controlling eye movements. Most children with A-T develop characteristic telangiectases - dilated blood vessels on the surfaces of their eyes and facial skin. As the disease progresses, the individual's immune system weakens, leading to recurrent respiratory infections and, at a later stage, predisposition to leukemia and lymphomas and a profound sensitivity to radiation exposure. People with A-T usually die in their teens or early 20s.

The identification of a single gene responsible for A-T may have practical benefits in the near future, such as allowing clinical geneticists to offer reliable diagnostic tests - including prenatal diagnosis and carrier detection - to all A-T families.

"Families of children with A-T will be thrilled that the culpable gene has been isolated," says Brad Margus, the father of two sons with A-T, and president of the A-T Children's Project, a non-profit organization based in Boca Raton, Florida that contributed to this study. "We now need to quickly clarify how this gene does its brutal damage so that some treatment can be designed."

The discovery of the ATM gene could also give scientists a way to identify the carriers of A-T mutations in the general population. According to Francis Collins, M.D., Ph.D., director of the NHGRI and a collaborator in the study, the ability to identify A-T carriers will give researchers an important to tool to help study the apparent increase in cancer risk among such carriers. "Concerns about increased radiation sensitivity in carriers can now be studied," he said. "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, said Collins, finding all of them, and determining which DNA alterations contribute to disease and which are harmless variations, will be necessary before a reliable test can be developed.

Both NINDS and NHGRI are components of the National Institutes of Health (NIH), located in Bethesda, Maryland. The NINDS is the nation's principal supporter of research on the brain and nervous system and a lead agency for the Congressionally designated Decade of the Brain. The institute supports and conducts a broad program of basic and clinical neurological investigations. NHGRI oversees NIH's role in the HGP, an international research effort to develop tools for gene discovery and analysis, and applies these technologies to the study of human genetic disease.

The research reported in Science is the result of collaboration among some 30 scientists around the world, with additional funding from the A-T Medical Research Foundation, the Thomas Appeal (A-T Medical Research Trust), the United States-Israel Binational Science Foundation, and others.

Yosef Shiloh

Tel Aviv University

Marian Emr
National Institute of Neurological Disorders and Strokes (NINDS)
Phone: (301) 496-5924
E-mail: me20t@nih.gov

Brad Margus
A-T Children's Project
Phone: (407) 483-2661

Leslie Fink
NHGRI Communications Office

Last updated: May 10, 2010