An international scientific team led by the University of Cambridge reports the identification of a gene essential to the production of pain-sensing neurons in humans. The study (“Transcriptional regulator PRDM12 is essential for human pain perception”), published in Nature Genetics, could have implications for the development of new methods of pain relief.
Pain perception is an evolutionarily-conserved warning mechanism that alerts us to dangers in the environment and to potential tissue damage. However, rare individuals are born unable to feel pain. These people accumulate numerous self-inflicted injuries, often leading to reduced lifespan.
Using detailed genome mapping, two teams of researchers collaborated to analyze the genetic make-up of 11 families across Europe and Asia affected by an inherited condition known as congenital insensitivity to pain (CIP). This enabled them to pinpoint the cause of the condition to variants of the gene PRDM12. Family members affected by CIP carried two copies of the variant; however, if they had only inherited one copy from their parents, they were unaffected.
The team looked at nerve biopsies taken from the patients to see what had gone wrong and found that particular pain-sensing neurons were absent. From these clinical features of the disease, the team predicted that there would be a block to the production of pain-sensing neurons during the development of the embryo. They confirmed this using a combination of studies in mouse and frog models, and in human induced pluripotent stem cells.
PRDM12 had previously been implicated in the modification of chromatin, a small molecule that attaches to our DNA and acts like a switch to turn genes on and off. The researchers showed that all the genetic variants of PRDM12 in the CIP patients blocked the gene's function. As chromatin is particularly important during formation of particular neurons, this provides a possible explanation for why pain-sensing neurons do not form properly in the CIP patients.
“PRDM2 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics,” wrote the investigators.
“The ability to sense pain is essential to our self-preservation, yet we understand far more about excessive pain than we do about lack of pain perception,” says Geoff Woods, M.D, from the Cambridge Institute for Medical Research at the University of Cambridge, who co-led the study. “Both are equally important to the development of new pain treatments. If we know the mechanisms that underlie pain sensation, we can then potentially control and reduce unnecessary pain.”
PRDM12 is only the fifth gene related to lack of pain perception to have been identified to date. However, two of the previously-discovered genes have already led to the development of new pain killers that are currently been tested in clinical trials.