What lies at the bottom of chromosome 11?

Thanks to the efforts of two mothers, an international research team has tracked down the defective gene that causes a very rare disease. Ruth McKernan reports

Scientific discoveries are usually driven by highly motivated university professors or keen researchers, rarely by the determined efforts of two British mothers.

Last month, an international team of scientists found the defective gene that causes a rare heritable disorder, Ataxia Telangiectasia (A-T). For researchers, finding the gene for A-T has been likened to the discovery of the Rosetta Stone. It will help unravel the fundamentals of cell biology, generating new insights into common human conditions as diverse as cancer and ageing. It may also cast light on how radiation causes cancer and why some people are more sensitive to radiation than others.

For the families of children who suffer from A-T, the discovery is a sign of hope and a reward for past efforts. For Beverley Hodson and Glynis Watkins in particular, it is a milestone that stands testimony to years spent fundraising and pushing for progress. Their families are two out of only about 100 in the UK whose children suffer from this progressive degenerative disorder.

Mrs Hodson's seven-year-old son, Thomas, is typical. His parents first noticed that, as a toddler, he was unsteady on his feet. At two, he was diagnosed with A-T and cancer. By the time he is a teenager he may well be in a wheelchair, like Mrs Watkins's 15-year-old daughter, Sian. As the disease progresses, children have problems eating, writing and speaking as well as walking. This is due to degeneration of nerves in the cerebellum, the rear part of the brain responsible for movement and limb control.

The disease gets its forbidding name from two symptoms that are characteristic of the disorder: "Ataxia" - the inability to control body movements - and "Telangiectasia", which describes dilation of blood vessels in the whites of the eye and the face.

According to Dr Malcolm Taylor from the Institute of Cancer Studies at the University of Birmingham, one of the team that found the gene, there are a host of further complications. "A-T patients are remarkable for their variety of clinical features," he says. The unusual list includes abnormalities of the liver, gonads, and endocrine system, susceptibility to cancer and infection as well as showing signs of premature ageing.

Another intriguing symptom is that patients are unusually sensitive to damage from X-rays. Some have died from relatively low doses of radiotherapy used to treat the cancer associated with A-T.

Mrs Hodson founded the A-T Research Trust in an effort to find out more about the disease. The trust has raised more than pounds 350,000 and supported work in Professor Yosef Shiloh's laboratory at the Sackler School of Medicine in Tel Aviv, where the gene was finally isolated, and in Dr Taylor's laboratory. Mrs Hodson got to know the scientists personally. "It is the flow of information that is so important and it is the human element which provides the spark to push things along," she says.

The most difficult question for researchers was how one defective gene could cause so many problems. "Finding the A-T gene was more important than just finding a gene for a rare disease; it would teach us more about the fundamentals of biology," says Sandy Raeburn, Professor of Clinical Genetics at the University of Nottingham, who heads the world's only specialist A-T clinic.

That clinic was launched in 1993 by Mrs Watkins and the A-T Society along with the Nottingham team to improve awareness and management of the disease. "With something this rare, specialists have seen few cases, and we hoped it would become a centre of excellence," she says. The clinic did more than that. It also provided researchers with a precious resource: easy access to a pool of patients to study.

Affected families provided blood samples for Dr Taylor's laboratory and others to analyse. "We knew the disease was inherited as a recessive disorder," he says. "This means both parents of an affected child are carriers, with one defective gene and one normal gene each. They have a one-in-four chance of their child developing A-T, which will happen if it inherits the defective gene from both parents."

Tracking down a mutant gene has become a long but now well-trodden path for geneticists. "First, you have to find out which chromosome the gene is on, then which region of the chromosome the gene is in," says Dr Taylor. The final step is to decide which of many candidate genes in that area of the genome is the culprit.

By 1988, an American group had tracked the gene to the bottom third of chromosome 11. Dr Taylor's team then refined the location, pinpointing a specific region between two distinct genetic markers. Until the beginning of this year, scientists in Israel, the US and the UK worked together as a consortium. Once the gene had been tracked to a small region, they split up and examined individual candidate genes in detail.

Professor Yosef Shiloh in Tel Aviv hit the jackpot. First, he found that every member of one family with A-T was missing part of a particular gene, then that other families had defects in the same gene, too. Scientists are relieved that they need not look further. Every patient so far examined has an error in the same gene, although there are a variety of different mutations. The spectrum of symptoms also varies. Professor Raeburn hopes that comparing the clinical and genetic profiles of sufferers will explain how the mutations are manifest. This should provide more information for families about their prognosis as well as scientific understanding of the gene's role.

When the scientists looked more carefully at the gene's properties, the pieces of the puzzle began to fall into place. For one thing, the gene is huge. It contains the instructions to make a very large protein, about 100 times bigger than the complex hormone insulin. The product of the A-T gene is a completely new and unstudied cell component, but it has structural similarities to several better understood molecules, raising many interesting questions. Part of the A-T gene product looks like an intracellular signalling molecule called PI-3kinase, which is important in cell division and growth. Could a defect in this part of the gene be linked to the leukaemia sometimes seen in A-T patients or to the unexplained death of cells in the brain that cause ataxia? Now that the gene has been found, there are still more questions to answer.

Scientists should soon be able to develop a diagnostic test to identify carriers more accurately. Currently, it is estimated that 0.5-1 per cent of the population are carriers, and these people run a higher risk of developing cancer, particularly breast cancer in women. The danger for carriers is not only from the cancer but also potentially from increased sensitivity to radiation treatment.

"We can say to people who have supported us that we have achieved something tangible. For us, finding the gene is like finding the energy for the rest of the journey," says Mrs Hodson.

Further information is available from the A-T Society, 33 Tuffnells Way, Harpenden, Hertfordshire AL5 3HA, and from the A-T Research Trust, Angel Cottage, School Lane, Colston Bassett, Nottingham.