“The Family That Feels Almost No Pain: An Italian Clan’s Curious Insensitivity to Pain Has Piqued the Interest of Geneticists Seeking a New Understanding of How to Treat Physical Suffering”, 2019-05 (; backlinks):
[Profile of the Marsili family, an Italian family which has a genetic mutation which renders pain far less painful but still felt: outright pain insensitivity is often fatal, but the Marsili condition is more moderate and so they are all alive and health, albeit much more injury-prone, like during skiing or sunbathing or childhood. In that condition, acute pain is felt, but then it fades and no chronic pain lingers. Scientists who had previously discovered a pain-insensitivity mutation in a Pakistani family (some dead) examined the Marsilis next, after years of testing candidate mutations, finally finding a hit which gene, when mutation of it were genetically engineered into mice, produced dramatically different, and the Marsili mutation specifically increased pain toleration.]
The broad import of their analysis is that it showed that ZFHX2 was crucially involved in pain perception in a way nobody had previously understood. Unlike more frequently documented cases of pain insensitivity, for instance, the Marsili family’s mutation didn’t prevent the development of pain-sensing neurons; those were still there in typical numbers. Yet it was also different from the Pakistani family’s mutation, whose genetic anomaly disabled a single function in pain-sensing neurons. Rather, ZFHX2 appeared to regulate how other genes operated, including several genes already linked to pain processing and active throughout the nervous system, including in the brain—a sort of “master regulator”, in the words of Alexander Chesler, a neurobiologist specializing in the sensory nervous system at the National Institutes of Health, in Bethesda, Maryland, who was not involved in the study.
“What’s so exciting is that this is a completely different class of pain insensitivity”, Chesler says. “It tells you that this particular pathway is important in humans. And that’s what gets people in the industry excited. It suggests that there are changes that could be made to somebody to make them insensitive to chronic pain.”