Found: Gene central to pain perception

A research team led by C. Geoffrey Woods, a physician at the Cambridge Institute for Medical Research in Cambridge, England, reports in today’s Nature that they have identified a genetic defect in some of the boy’s relatives who are also unable to feel pain. The defect inactivates a gene that is critical to the body’s perception of pain. The gene presents an attractive target for drug developers seeking to eliminate pain.

Dr. Allan Basbaum, an expert on pain at the University of California, said the finding was “a very exciting story,” providing strong proof of the principle that inhibition of the gene “can result in powerful pain control with minimal side effects.”

But if drugs be developed, they should not eliminate the pain altogether because of its protective effects, he said.

Woods, who has patients among the Pakistani emigrant community in Britain, said he was told of the boy in one of his periodic visits to Pakistan. He decided to examine him on a later visit, but learned that the boy had died after jumping off the roof of a house to impress his friends.

Woods then looked to see if there were any other pain-free individuals in the Qureshi clan to which the boy belonged.

After much effort, Woods and his colleagues in Pakistan and Britain found three Qureshi families among whom six members reported that they had never experienced pain in any part of their body.

After six years of work, Woods found that the affected members of all three families had a defect in a gene known as sodium channel N9A, or SCN9A, one of a family of 11 human genes whose protein products govern the initiation of signals that nerves send in the body. They open channels that let sodium ions rush across a nerve cell’s membrane.

The SCN9A gene is active both in nerves that mediate pain and in those of the sympathetic nervous system, which controls vital bodily functions like heart rate. But for reasons that are not yet understood, the affected members of the Pakistani families had no symptoms of a disordered sympathetic nervous system, like irregular heart rate, and seemed entirely normal apart from the occasional self-inflicted damage caused by their inability to feel pain.

Woods’s discovery “is an important part of a fascinating story,” said Dr. Stephen G. Waxman, a neurologist at Yale University who studies erythromelalgia, a disease in which patients feel an intense burning sensation after exposure to mild warmth. This disease is also caused by mutations in the SCN9A gene, but ones that enhance the gene’s activity instead of blocking it.

Drug developers might find the gene particularly interesting because the defective form in the Pakistani patients seems to have no side effects, even in the sympathetic nervous system where they would be expected, Waxman said.