Molecular machinery in women who are pain-insensitive has been discovered via study.

New study from UCL has revealed the biochemistry of a rare genetic mutation that enables its carrier to live almost pain-free, heal more quickly, and experience less worry and fear.n

The research, which was published in the journal “Brain,” builds on the team’s 2019 discovery of the FAAH-OUT gene and its relationship to wound healing and mood. It is hoped that the results may identify new therapeutic targets and open up new directions for this type of study.n

Jo, who lives in Scotland, was first referred to pain geneticists at UCL in 2013, after her doctor noticed that she experienced no pain after major surgeries on her hip and hand. After six years of searching, they identified a new gene that they named FAAH-OUT, which contained a rare genetic mutation. In combination with another, more common mutation in FAAH, it was found to be the cause of Jo’s unique characteristics.n

The area of the genome containing FAAH-OUT had previously been assumed to be “junk” DNA that had no function, but it was found to mediate the expression of FAAH, a gene that is part of the endocannabinoid system and that is well-known for its involvement in pain, mood and memory.n

In this study, the team from UCL sought to understand how FAAH-OUT works at a molecular level, the first step towards being able to take advantage of this unique biology for applications like drug discovery.n

This included a range of approaches, such as CRISPR-Cas9 experiments on genes, as well as analyzing the expression of genes to see which were active in molecular pathways involved with pain, mood and healing.n

The team observed that FAAH-OUT regulates the expression of FAAH. When it is significantly turned down as a result of the mutation carried by Jo Cameron, FAAH enzyme activity levels are significantly reduced.n

Dr. Andrei Okorokov (UCL Medicine), a senior author of the study, said, “The FAAH-OUT gene is just one small corner of a vast continent, which this study has begun to map. As well as the molecular basis for painlessness, these explorations have identified molecular pathways affecting wound healing and mood, all influenced by the FAAH-OUT mutation. As scientists it is our duty to explore and I think these findings will have important implications for areas of research such as wound healing, depression and more.”n

The authors looked at fibroblasts taken from patients to study the effects of the FAAH-OUT-FAAH axis on other mutations that Jo Cameron carries turn down FAAH, they also found a further 797 genes that were turned up and 348 that were turned down. This included alterations to the WNT pathway that is associated with wound healing, with increased activity in the WNT16 gene that has been previously linked to bone regeneration.n

Two other key genes that were altered were BDNF, which has previously been linked to mood regulation and ACKR3, which helps to regulate opioid levels. These gene changes may contribute to Jo Cameron’s low anxiety, fear and pain.n

Professor James Cox (UCL Medicine), a senior author of the study, said, “The initial discovery of the genetic root of Jo Cameron’s unique phenotype was a eureka moment and hugely exciting, but these current findings are where things really start to get interesting. By understanding precisely what is happening at a molecular level, we can start to understand the biology involved and that opens up possibilities for drug discovery that could one day have far-reaching positive impacts for patients.”

More information:
Hajar Mikaeili et al, Molecular basis of FAAH-OUT-associated human pain insensitivity, Brain (2023). DOI: 10.1093/brain/awad098

Journal information:

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University College London

Study reveals unique molecular machinery of woman who can’t feel pain (2023, May 23)
retrieved 23 May 2023

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