Scientists have learned more about a genetic disorder caused by a mutation in a gene called FAAH-OUT, in which carriers feel minimal or no pain, anxiety, or fear. The mutation reduces the expression of the gene and its associated protein, impacting biochemical pathways that are related to mood and wound healing. The researchers suggested that this work, which has been reported in the journal Brain, could help scientists identify new strategies to treat chronic pain.
Patient Jo Cameron underwent major surgeries on her hip and hand but had no pain afterwards. Doctors referred her to pain geneticists, and although it took six years, a mutation in a newly identified gene called FAAH-OUT was eventually determined to be the cause of this characteristic. This region of DNA that carried the mutation was once thought not to code for protein; it was thought of as so-called junk DNA. However, this sequence actually encodes for a long, non-coding RNA that modifies the expression of another gene that has previously been found, called FAAH. Jo Cameron was also found to carry a variant in FAAH as well, which also reduces FAAH expression.
FAAH is a member of the endocannabinoid system and has a well-known role in memory, mood, and pain.
In this work, the researchers modeled the patient's mutation using the CRISPR-Cas9 gene editor, and also performed a gene expression analysis. This showed that FAAH-OUT, the long non-coding RNA (lncRNA), regulates the expression of FAAH. The enzymatic activity of FAAH was significantly reduced because of the mutation in FAAH-OUT.
Other pathways seemed to be affected by the genetic mutations seen in the patient, including one known as Wnt. This pathway has a variety of roles, but is known to be involved in wound healing. Other affected genes included BDNF, which is related to mood and cognition, and ACKR3, which is related to opioid level regulation. These genetic changes could help explain the low levels of anxiety, fear, and pain that are experienced by Jo Cameron.
"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," noted co-corresponding study author Professor James Cox of UCL Medicine. "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."
Sources: University College London, Brain
