Out of control

A breakdown in one of the body's gene-regulation mechanisms may cause a mental disorder in children. Steve Connor assesses the implications

Two independent teams of scientists have coincidentally stumbled across a discovery that could explain the cause of the most commonly inherited mental disorder of children. Both teams have found evidence to suggest that the gene responsible for Fragile X syndrome – which affects one in 4,000 boys, and one in 6,500 girls – is directly involved in a newly discovered phenomenon that is revolutionising medical science.

The scientists are proposing that Fragile X syndrome could be the first human disease shown to be caused by a defect in one of the body's natural mechanisms for controlling genes – called RNA interference. RNAi is viewed as one of the most exciting developments in biology because it appears to be one of the ways that human cells can switch off genes without affecting the DNA of the chromosomes in the cell's nucleus.

Scientists are already working on ways of exploiting the discovery to switch off the genes of invading viruses, such as HIV, or turning off human genes involved with triggering the growth of cancerous tumours. Now, two groups of scientists, one led by Haruhiko Siomi of the University of Tokushima, another led by Gregory Hannon of Cold Spring Harbour Laboratory in New York, have discovered that defects in the RNAi process are also likely to be involved in causing an incurable inherited disorder. If their suggestion is correct then it could lead to new treatments for the thousands of children with Fragile X syndrome who suffer from mild to severe language and learning difficulties. Fragile X syndrome often goes undiagnosed until a child is quite old, even though parents are aware that things are not as they should be.

This was the case with Jonathan Southwell, 19, who was not diagnosed with Fragile X syndrome until he was 10, despite having quite severe learning problems. His mother, Brighid Southwell, took him "from pillar to post" to find out what was wrong, and it wasn't until she offered to pay for a brain scan that doctors thought of doing a chromosome test. "We had problems from the start, and at seven he went to a special school because he wasn't able to keep up with his class," says Southwell, a former lawyer living in London. "When we got a diagnosis, we were concerned about our other children [three younger daughters], but blood tests were negative," she said.

Discovering that Jonathan was a sufferer caused Southwell to track down her relatives, many in New Zealand. Tests showed that 17 were either carriers or affected by the condition, and none had been diagnosed. "Knowing the diagnosis has been good, it's taken pressure off Jonathan, it helps me to understand him, and I got support from the Fragile X Society," she says.

The gene responsible for Fragile X syndrome produces a protein that is believed to regulate other critical genes involved in the normal development of a child's nervous system. A similar gene also exists in the fruit fly, and it is this gene that the two research teams worked on. To their surprise, they found that the protein from this fruit-fly gene is directly involved in the RNAi process, leading them to suspect that the Fragile X gene in humans regulates other developmental genes using RNAi also.

If so, it would mean that Fragile X syndrome is a direct result of the RNAi process going awry: a discovery that could lead to better treatment for the currently incurable disorder. The latest research suggests that there may be other inherited diseases resulting from the disruption of RNAi in human cells, a finding that is likely "to open a new field of molecular human genetics: defects in an RNAi-related apparatus that cause disease," says Dr Siomi.

The work of both teams is published side by side in the journal Genes and Development to emphasise the independence of the two sets of findings. For people affected by the syndrome, such as Jonathan and his mother, the findings cannot provide immediate help. Yet the research may lead to a greater insight into the condition that could result in a cure.

For information: www.fragilex.org.uk