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Genes can make you pain free. And it is not a good thing. Researchers led by experts from the University College, London have identified a rare mutation in an Italian family that prevent all of them from feeling pain. The findings, published in the journal Brain could be used to identify new treatments for chronic pain. “The members of this family can burn themselves or experience pain-free bone fractures without feeling any pain. But they have a normal intraepidermal nerve fibre density, which means their nerves are all there, they’re just not working how they should be. We’re working to gain a better understanding of exactly why they don’t feel much pain, to see if that could help us find new pain relief treatments,” said the study’s lead author, Dr James Cox of UCL Wolfson Institute for Biomedical Research. Pain is defined as an unpleasant sensation that can range from mild, localized discomfort to agony. While it is widely recognised that it can have both physical and emotional components, pain has a very important physiological role to play; it signals that something is not right with the body. That is why it is now recognised as the fifth vital sign, after temperature, heart rate, blood pressure and respiration rate. One in ten people experience moderately to severely disabling chronic pain, but treatments beyond common painkillers remain elusive. Understanding the causes of congenital analgesia, a rare inherited condition that reduces the capacity to feel physical pain, is one of the main areas of research that could lead to new pain relief therapies. Two other mutations causing congenital analgesia are being actively explored by researchers alongside pharmaceutical firms, but have yet to yield any breakthrough drugs. The research team added to previous work with the Italian family to clarify the nature of their phenotype (the observable characteristics caused by their genetics) – named the Marsili syndrome after their surname – finding that they’re hyposensitive to noxious heat, hyposensitive to capsaicin (in chilli peppers) and have experienced pain-free bone fractures. Using DNA from blood samples, the researchers conducted a whole exome sequencing – mapping out the protein-coding genes in the genome of each family member. They identified a novel point mutation in the ZFHX2 gene. The mutation alters a part of the gene’s protein sequence that is normally consistent across species as variable as mice and frogs. “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. 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,” said co-author Professor Anna Maria Aloisi (University of Siena), who was part of the team that initially identified the Marsili family’s distinctive condition.