Scientists have identified a mysterious genetic mutation that effectively negates the sensation of pain, enabling people with the rare anomaly to persevere effortlessly through extreme physical discomfort.
The gene variant – identified in an Italian family who feels almost no pain even when seriously injured – could help scientists find new treatments for chronic pain that mimic the family's unusual gift.
"We have spent several years trying to identify the gene that is the cause of this," molecular biologist James Cox from University College London told The Independent.
"This particular disorder may only be in one family."
That family, the Marsilis, go about their daily lives with something much like a real-life superpower, thanks to a rare genetic point mutation spanning at least three generations.
The mutation means they feel little or no pain from things like burns or broken bones, to the point where they don't always actually realise when they've been hurt.
"Sometimes they feel pain in the initial break but it goes away very quickly," Cox told New Scientist.
"For example, [52-year-old] 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."
The variant shared by the family was isolated in the Marsilis' DNA from blood samples, and is located in a gene called ZFHX2.
While it's not entirely clear how the mutation works, the team hypothesises that the variant disrupts how ZFHX2 regulates other genes that have been linked to pain signalling.
That disruption gives the Marsilis what's known as congenital insensitivity to pain, but their phenotype is so remarkable the researchers have named a whole sub-type of the condition, 'Marsili syndrome', after the family.
In the Marsilis' case, the blessing can also be a curse, as the failure to accurately interpret what pain represents can mean they're not aware of serious injuries that might need medical attention.
For example, Letizia Marsili's 24-year-old son, Ludovico, plays football, and the condition masks injuries incurred by the sport.
"He rarely stays on the ground, even when he is knocked down. However, he has fragility at the ankles and he often suffers distortions, which are micro fractures," Letizia Marsili told the BBC.
"In fact, recently X-rays have shown that he has lots of micro fractures in both ankles."
Other family members have experienced similar problems, with Letizia's 78-year-old mother experiencing fractures that are only much later diagnosed, meaning they harden naturally but do not heal properly.
The mutation also affects their ability to detect extreme temperatures, putting them at greater risk of burning themselves, or failing to register things like ice water.
Despite the risks inherent in feeling no pain, the family seems grateful to be missing out on what is a source of misery for so many others.
"From day to day we live a very normal life, perhaps better than the rest of the population, because we very rarely get unwell and we hardly feel any pain," Letizia told the BBC.
"However, in truth, we do feel pain, the perception of pain, but this only lasts for a few seconds."
Once the researchers isolated the ZFHX2 mutation by way of exome sequencing, the team used animal experiments to see how the variant affects pain processing in mice.
Animals bred to not have the gene at all showed reduced pain sensitivity when pressure was applied to their tails, but were still receptive to high heat.
When other mice were bred to possess the ZFHX2 mutation, they exhibited the same low sensitivity to high heat that the Marsilis have – something the team is hopeful may provide new directions into treatments for millions who live with chronic pain daily.
"By identifying this mutation and clarifying that it contributes to the family's pain insensitivity, we have opened up a whole new route to drug discovery for pain relief," says one of the researchers, Anna Maria Aloisi from the University of Siena in Italy.
"With more research to understand exactly how the mutation impacts pain sensitivity, and to see what other genes might be involved, we could identify novel targets for drug development."
There's a lot to still find out about how ZFHX2 is involved in pain signalling, but as far as one family is concerned at least, they won't not hanging by the phone to hear about any future discoveries.
One of the researchers, sensory neurobiologist John Wood from University College London, says the family has no intention of ever giving up their painless existence, should scientists one day figure out a way of reversing the condition.
"I asked them if they would like to normally sense pain," he told New Scientist, "and they said no."
The findings are reported in Brain.