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Rare gene mutation gives rise to low sensitivity to pain

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By Kate Bass, BScDecember 15, 2017

Researchers at University College London have identified a rare gene mutation in an Italian family who have little sensitivity to some forms of pain. Chronic pain caused by conditions such as lower back pain and osteoarthritis is one of the most prominent causes of disability worldwide, as assessed by the Global Burden of Disease reviews.

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The members of this family can burn themselves or experience bone fractures without feeling any pain. But they have a normal intra-epidermal 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".
Dr James Cox, UCL Wolfson Institute for Biomedical Research

In addition to severely impacting a patients quality of life, it can be associated with severe economic burden due to works days lost. Severe pain can also be a barrier to recovery and a cause of depression. Furthermore, chronic pain is suffered by a significant proportion of the population, with between one-third and one-half of the UK population having chronic pain.

However, despite the well documented wide-reaching negative impacts of chronic pain, there has been little progress in recent years in pain management strategies. These continue to be based on the administration of analgesic medication such as non-steroidal anti-inflammatory drugs and opioid-based medications.

Novel strategies for pain management are thus being explored. One such area of research is congenital hypoalgesia, an inherited disorder which causes patients to have a severely reduced capacity to detect damage to their body that would usually cause extreme pain, such as biting off fingertips, lips and the tongue, and frequent bone fractures. Patients with such pain insensitivity are being assessed in the hope of identifying novel analgesic drug targets.

Researchers at University College London have been studying an Italian family, the Marsilis, which has six members with a distinctive pain response that has not been observed in any other people. These individuals do not feel noxious heat or the burn of capsaicin in chilli peppers, and have experienced pain-free bone fractures.

By mapping all the protein-coding genes in the genome of each family member, the researchers have identified a novel point mutation in the . The mutation occurs in a part of the gene sequence that is normally remarkably constant, even across different species.

To assess the function of this gene, they developed a mouse model in which the ZFHX2 gene was entirely absent. These mice had increased pain thresholds. Mice with the Marsilis' mutation were found to be insensitive to high temperatures. Further such analyses have shown that the ZFHX2 gene is responsible for regulating various other genes involved in pain signalling.

Dr Abdella Habib of Qatar University, who conducted the study while based at UCL, commented."We hope that our findings and the subsequent research projects will help find better treatments for the millions of people worldwide who experience chronic pain and don't get relief from existing drugs".

These findings will be used to identify new treatments for chronic pain, with one potential option being gene therapy.

Sources:

Habib AM, et al. A novel human pain insensitivity disorder caused by a point mutation in ZFHX2. Brain 2017. Published online December 2107. Available at: https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awx326/4725107
University College London Press Release 13 December 2107. Available at https://eurekalert.org/pub_releases/2017-12/ucl-gmc121317.php