Gene Mutations that Cause CIP

By Julia Brittain

            Although the idea of and experiences associated with pain leave people with negative perceptions of it, feeling pain is essential for human survival. The experience of pain within the human body serves as an “alarm system,” and allows humans to recognize, react to, and in the future, avoid stimuli that create pain in the first place. Nociception is the process through which the sensory nervous system senses and perceives painful stimuli, which then allows for the triggering of appropriate reactions. Nociceptors, sensory receptors for painful stimuli, play a key role within this process. The nociceptive fibers within the skin, muscle, and skeletal structures, send signals back to their cell bodies in the spinal cord and form synapses in the dorsal horn of the spinal cord; the signal is then sent to the brain where it is processed within the cerebral cortex. There, a reaction to the pain is developed and a signal carrying that response is sent back to where the pain originated (Garland, 2012). Unfortunately, this vital process of pain perception can be inhibited by certain gene mutations that cause people to have a congenital insensitivity to pain, also known as CIP.

            CIP is a condition that inhibits the body’s ability to perceive pain, and it is considered a form of peripheral neuropathy given its impact on the peripheral nervous system. People who suffer from this condition are able to feel the stimulus, but are unable to perceive the associated pain; for example, one is able to differentiate between hot and cold beverages, but one is unable to feel if the hot beverage is burning one’s mouth (Cox, 2017). People who suffer from CIP can often end up biting their tongue or breaking a bone without realizing that they are hurting themselves, which can lead to prolonged periods with untreated injuries. The inability to perceive pain stems from non-functional alpha subunits within the NaV1.7 voltage-gated sodium channels in the nociceptors. Sodium channels are a key part in a cell’s ability to generate action potentials and thus send out neurotransmitters because they are responsible for mediating the transport of sodium ions into the cells. The gene mutations associated with CIP result in a nonfunctional alpha subunit within the sodium channel, and therefore the channels are incapable of sodium transport, which prevent the nociceptors from transmitting pain signals to the brain (Drenth & Waxman, 2007).

            The gene most well known for carrying the mutations that causes CIP is the SCN9A gene, which is the gene responsible for the alpha subunits within the sodium channels. SCN9A, a protein-coding gene, stands for sodium voltage-gated channel alpha subunit 9 (“SCN9A Gene,” 2012). The SCN9A carries up to 13 different mutations—all of which lead to having a congenital insensitivity to pain. A mutation within the SCN9A gene causes the formation of the alpha subunit to stop prematurely, which renders the sodium channel dysfunctional, as the subunit and channel are incompatible (Drenth & Waxman, 2007). Mutations within the SCN9A gene can also lead to other pain disorders such as erythromelalgia, paroxysmal extreme pain disorder, and small fiber neuropathy (“SCN9A Gene,” 2012).

            SCN11A is another gene known to carry mutations that can lead to CIP. Similar to SCN9A, SCN11A’s role is to encode the Nav1.9 sodium channels in order to relay pain signals. With a mutation within SCN11A, the sodium channel is over active, which results in sustained depolarization of the nociceptors thus obstructing the generation of normal action potentials (Leipold et al., 2013). The most recent gene discovered to be linked to CIP is the PRDM12 gene; the PRDM12 gene holds 10 known mutations that can cause CIP. The PRDM12 gene is responsible for the transcriptional regulation of sensory neuronal specification, and the gene’s proteins are also responsible for neurogenesis (Chen et al., 2015). The gene mutation is also related to hereditary sensory and autonomic neuropathies (“PRDM12 Gene,” 2012). These three genes hold the majority of the known mutations that lead to CIP, but the number of gene mutations rise substantially for those who suffer from CIPA, which is congenital insensitivity to pain with anhidrosis, abnormal perspiration.

            Although there is currently little hope for a cure of CIP, the disease might be the key to creating a new painkiller with few side effects. Pharmaceutical companies have embarked on a mission to find and develop drugs that can inhibit the Nav1.7 sodium channel as a method of treatment of the chronic and other types of pain (Yekkirala, Roberson, Bean, & Woolf, 2017). Through the generation of artificial sodium channel blockers, pharmaceutical companies are hoping to create an entirely new class of painkillers that act solely on the peripheral nervous system in order to modulate stimulus response without impacting cognitive response (Crow, Denk, & McMahon, 2013). In the early stages of research and development, many researchers have determined that the main hurdle is finding antibodies that will bind to as well as inhibit the ion channels (Cox, 2017). Although no formal solution has been derived from these studies yet, researchers are hopeful that they will soon be able to better understand the Nav1.7 sodium channel and develop molecules that effectively inhibit it.

            Although the concept of living a painless life might paint CIP in a desirable light, the sensation of pain is necessary for a healthy and safe life. Mutations within genes of SCN9A, SCN11A, and PRDM12 are the main causes of malformations of the sodium channels within the nociceptors, which ultimately result in an inability to feel pain. Although there are no current cures or treatments for CIP, the disease does offer a possible solution for treating pain in the future; through targeting the Nav1.7 sodium channel, pharmaceutical companies are working towards creating a drug that blocks the channel similarly to CIP. With a better understanding of the mechanisms of both the sodium channels and the condition itself, great strides within the medical community could be made towards creating more effective methods of pain treatment and, hopefully, developing a solution to CIP.

References

Chen, Y. C., Auer-Grumbach, M., Matsukawa, S., Zitzelsberger, M., Themistocleous, A. C., Strom, T. M., ... & Weiss, C. (2015). Transcriptional regulator PRDM12 is essential for human pain perception. Nature Genetics, 47(7), 803-808.

Cox, D. (2017, April 17). The curse of people who never feel pain [Editorial]. Retrieved August 12, 2018, from BBC Biology website: http://www.bbc.com/future/story/20170426-the-people-who-never-feel-any-pain

 Crow, M., Denk, F., & McMahon, S. B. (2013). Genes and epigenetic processes as prospective pain targets. Genome medicine, 5(2), 12.

Drenth, J. P. H., & Waxman, S. G. (2007). Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. The Journal of Clinical Investigation, 117(12), 3603–3609. http://doi.org/10.1172/JCI33297

Garland, E. L. (2012). Pain processing in the human nervous system: A selective review of nociceptive and biobehavioral pathways. Primary Care: Clinics in Office Practice, 39(3), 561–571. http://doi.org/10.1016/j.pop.2012.06.013

Leipold, E., Liebmann, L., Korenke, G. C., Heinrich, T., Gießelmann, S., Baets, J., ... & Bergmann, M. (2013). A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nature Genetics, 45(11), 1399.

PRDM12 Gene. (2012). In Genetics Home Reference database. Retrieved from https://ghr.nlm.nih.gov/gene/PRDM12

SCN9A Gene. (2012). In Genetics Home Reference database. Retrieved from https://ghr.nlm.nih.gov/gene/SCN9A

Yekkirala, A. S., Roberson, D. P., Bean, B. P., & Woolf, C. J. (2017). Breaking barriers to novel analgesic dr