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.

Start your day with The Independent, sign up for daily news emails
Arts and Entertainment
musicOfficial chart could be moved to accommodate Friday international release day
Wes Brown is sent-off
Italy celebrate scoring their second try
six nations
Glenn Murray celebrates scoring against West Ham
footballWest Ham 1 Crystal Palace 3
Arts and Entertainment
Drake continues to tease ahead of the release of his new album
ebooksA special investigation by Andy McSmith
Latest stories from i100
Have you tried new the Independent Digital Edition apps?
Independent Dating

By clicking 'Search' you
are agreeing to our
Terms of Use.

iJobs Job Widget
iJobs General

Recruitment Genius: Bookkeeper / Office Co-ordinator

£9 per hour: Recruitment Genius: This role is based within a small family run ...

Recruitment Genius: Designer - Print & Digital

£28000 - £32000 per annum: Recruitment Genius: This Design and marketing agenc...

Recruitment Genius: Quantity Surveyor

£46000 per annum: Recruitment Genius: This property investment firm are lookin...

Recruitment Genius: Telesales / Telemarketing Executive - OTE £30k / £35k plus

£18000 - £35000 per annum: Recruitment Genius: This company specialises provid...

Day In a Page

The Last Word: For the good of the game: why on earth don’t we leave Fifa?

Michael Calvin's Last Word

For the good of the game: why on earth don’t we leave Fifa?
HIV pill: Scientists hail discovery of 'game-changer' that cuts the risk of infection among gay men by 86%

Scientists hail daily pill that protects against HIV infection

Breakthrough in battle against global scourge – but will the NHS pay for it?
How we must adjust our lifestyles to nature: Welcome to the 'Anthropocene', the human epoch

Time to play God

Welcome to the 'Anthropocene', the human epoch where we may need to redefine nature itself
MacGyver returns, but with a difference: Handyman hero of classic 1980s TV series to be recast as a woman

MacGyver returns, but with a difference

Handyman hero of classic 1980s TV series to be recast as a woman
Tunnel renaissance: Why cities are hiding roads down in the ground

Tunnel renaissance

Why cities are hiding roads underground
'Backstreet Boys - Show 'Em What You're Made Of': An affectionate look at five middle-aged men

Boys to men

The Backstreet Boys might be middle-aged, married and have dodgy knees, but a heartfelt documentary reveals they’re not going gently into pop’s good night
Crufts 2015: Should foreign dogs be allowed to compete?

Crufts 2015

Should foreign dogs be allowed to compete?
10 best projectors

How to make your home cinema more cinematic: 10 best projectors

Want to recreate the big-screen experience in your sitting room? IndyBest sizes up gadgets to form your film-watching
Manchester City 1 Barcelona 2 player ratings: Luis Suarez? Lionel Messi? Joe Hart? Who was the star man?

Manchester City vs Barcelona player ratings

Luis Suarez? Lionel Messi? Joe Hart? Who was the star man at the Etihad?
Arsenal vs Monaco: Monaco - the making of Gunners' manager Arsene Wenger

Monaco: the making of Wenger

Jack Pitt-Brooke speaks to former players and learns the Frenchman’s man-management has always been one of his best skills
Cricket World Cup 2015: Chris Gayle - the West Indies' enigma lives up to his reputation

Chris Gayle: The West Indies' enigma

Some said the game's eternal rebel was washed up. As ever, he proved he writes the scripts by producing a blistering World Cup innings
In Ukraine a dark world of hybrid warfare and murky loyalties prevails

In Ukraine a dark world of hybrid warfare

This war in the shadows has been going on since the fall of Mr Yanukovych
'Birdman' and 'Bullets Over Broadway': Homage or plagiarism?

Homage or plagiarism?

'Birdman' shares much DNA with Woody Allen's 'Bullets Over Broadway'
Broadchurch ends as damp squib not even David Tennant can revive

A damp squib not even David Tennant can revive

Broadchurch, Series 2 finale, review
A Koi carp breeding pond, wall-mounted iPads and a bathroom with a 'wellness' shower: inside the mansion of Germany's 'Bishop of Bling'

Inside the mansion of Germany's 'Bishop of Bling'

A Koi carp breeding pond, wall-mounted iPads and a bathroom with a 'wellness' shower