The biology underpinning a rare genetic mutation that allows its carrier to live virtually pain-free, heal more rapidly and experience reduced anxiety and fear, has been uncovered by new research from UCL.
The study, published in Brain, follows up the team’s discovery in 2019 of the FAAH-OUT gene and the rare mutations that cause Jo Cameron to feel virtually no pain and never feel anxious or afraid. The new research describes how the mutation in FAAH-OUT ‘turns down’ FAAH gene expression, as well as the knock-on effects on other molecular pathways linked to wound healing and mood. It is hoped the findings will lead to new drug targets and open up new avenues of research in these areas.
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.
This included a range of approaches, such as CRISPR-Cas9 experiments on cell lines to mimic the effect of the mutation on other genes, as well as analyzing the expression of genes to see which were active in molecular pathways involved with pain, mood and healing.
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.
The authors looked at fibroblasts taken from patients to study the effects of the FAAH-OUT-FAAH axis on other molecular pathways. While the 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.
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 painlessness.
