A research team from UCL has identified a rare mutation that causes members of one family to have low sensitivity to pain. The researchers hope that the results could be used to identify new treatments for chronic pain.
One in ten people experience moderate to severe disabling chronic pain. Understanding congenital analgesia, a rare inherited condition that reduces the capacity to feel physical pain, could lead to new pain relief therapies. Two mutations causing congenital analgesia are being explored by researchers working with pharmaceutical firms, but no breakthrough drugs have been developed. The researchers studied an Italian family, the Marsilis, which has six people with a distinctive pain response unique to them. The members of this family can burn themselves without feeling any pain. The family has normal intraepidermal nerve fibre density which means they are not missing any nerves. The researchers were working to try to gain an understanding of why they don’t feel much pain. The research team added to previous work with the Italian family to clarify the nature of their phenotype, named the Marsili syndrome after their surname, finding they are hyposensitive to capsaicin (in chilli peppers), hyposensitive to noxious heat, and have experienced pain-free bone fractures.
Using DNA from blood samples, the researchers conducted a whole exome sequencing and mapped out the protein-coding genes in the genome of each family member. The researchers found a 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. The researchers conducted two animal studies to understand how the gene affects pain sensations in mice. Initially mice were used that had been bred with the ZFHX2 gene entirely absent, and were found to have altered pain thresholds. Mice that had the relevant mutation were notably insensitive to high temperatures. Further analysis of the mice bearing the mutation clarified that the gene regulates a number of other genes that have previously-established connections to pain signalling.
The researchers identified the mutation and clarified that it contributes to the pain insensitivity. Additional research still needs to be conducted to understand the impact on pain sensitivity, and to see what other genes might be involved. The researchers feel that novel drugs to treat pain could be developed from this work. One such treatment may be a gene therapy strategy that could mimic the Marsili phenotype by overexpressing the mutated transcription factor. Currently today millions of patients who suffer from chronic pain do not get enough relief from current drugs. Perhaps knowledge learned from studying the Marsilis could lead to new drugs that could help with chronic pain.
Reference: Cristina Elena Niturad et al., Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features. Brain, Dec. 2017.