Going unnoticed Peter Dazeley/Getty

An Italian family that is barely able to sense pain has had the genetic root of their shared disorder uncovered. Understanding this gene may lead to new painkiller drugs.

The affected family members include a 78-year-old woman, her two middle-aged daughters, and their three children. All of them fail to sense pain in the way most of us do, and don’t notice when they are being injured. When they were assessed, the family members were found to have bone fractures in their arms and legs that they hadn’t realised were there.

“Sometimes they feel pain in the initial break but it goes away very quickly,” says James Cox, of University College London. “For example, Letizia broke her shoulder while skiing, but then kept skiing for the rest of the day and drove home. She didn’t get it checked out until the next day.”


To find the cause of their lack of pain sensitivity, Cox and his colleagues performed a series of tests on the family members. The team found that all six individuals had normal numbers of nerves in their skin, but that they all had a mutation in a gene called ZFHX2.

When the team deleted this gene entirely in mice, they found that the animals were not as good at sensing when painful pressure was applied to their tails, but they were hypersensitive to heat sensations. This suggests the gene may play a role in controlling whether stimuli are painful or not.

Happily insensitive

The team then gave mice the same mutated version of the gene that the Italian family had. These mice were much less sensitive to painful levels of heat. The mutation seems to have this affect because the gene normally controls the activity of 16 other genes, some of which are involved in sensing pain.

Cox and his colleagues hope to work out exactly how these genes contribute to the reduced sensation of pain. Once they have, they might be able to develop drugs that achieve the same effect. Such drugs could benefit people in chronic pain, who often struggle to find relief with existing treatments.

It may also be possible to develop a treatment to reverse the family’s pain insensitivity. But team-member John Wood says the family told him they don’t want that. “I asked them if they would like to normally sense pain and they said no.”

Journal reference: Brain, DOI: 10.1093/brain/awx236

Read more: Woman who has never felt pain experiences it for the first time