Though references to the “sixth sense” often bring images of paranormal phenomena to mind, the scientific world has bestowed this title to our innate awareness of our own bodies in space. Proprioception, the official name of this sense, is what allows us to play sports and navigate in the dark. Like our other five senses, our capability for spatial awareness has become so automatic that we hardly ever think about it. But scientists at the National Institute of Health (NIH) have made some breakthroughs about a genetic disorder that causes people to lack this sense, leading to skeletal abnormalities, balance difficulties, and even the inability to discern some forms of touch.1
The gene PIEZO2 has been associated with the body’s ability to sense touch and coordinate physical actions and movement. While there is not a substantial amount of research about this gene, previous studies on mice show that it is instrumental in proprioception.2 Furthermore, NIH researchers have recently attributed a specific phenotype to a mutation in PIEZO2, opening a potential avenue to unlock its secrets.
Pediatric neurologist Carsten G. Bönnermann, the senior investigator at the NIH National Institute of Neurological Disorders and Stroke, had been studying two patients with remarkably similar cases when he met Alexander Chesler at a lecture. Chesler, an investigator at the NIH National Center for Complementary and Integrative Health, joined Bönnermann in performing a series of genetic and practical tests to investigate the disorder.1
The subjects examined were an 8-year-old girl and an 18-year-old woman from different backgrounds and geographical areas. Even though these patients were not related, they both exhibited a set of similar and highly uncommon phenotypes. For example, each presented with scoliosis - unusual sideways spinal curvature - accompanied by fingers, feet, and hips that could bend at atypical angles. In addition to these physical symptoms, the patients experienced difficulty walking, substantial lack of coordination, and unusual responses to physical touch.1These symptoms are the result of PIEZO2 mutations that block the gene’s normal activity or production. Using full genome sequencing, researchers found that both patients have at least one recessively-inherited nonsense variant in the coding region of PIEZO2.1 But because these patients represent the first well-documented cases of specific proprioceptive disorders, there is not an abundance of research about the gene itself. Available previous studies convey that PIEZO2 encodes a mechanosensitive protein - that is, it generates electrical nerve signals in response to detected changes in factors such as cell shape.2 This function is responsible for many of our physical capabilities, including spatial awareness, balance, hearing, and touch. In fact, PIEZO2 has even been found to be expressed in neurons that control mechanosensory responses, such as perception of light touch, in mice. Past studies found that removing the gene in mouse models caused intolerable limb defects.2 Since this gene is highly homogenous in humans and in mice (the two versions are 95% similar), many researchers assumed that humans could not live without the gene either. According to Bönnermann and Chesler, however, it is clear that this PIEZO2 mutation does not cause a similar fate in humans.
Along with laboratory work, Bönnermann and Chesler employed techniques to further investigate the tangible effects of the mutations. Utilizing a control group for comparison, the researchers presented patients with a set of tests that examined their movement and sensory abilities. The results were startling, to say the least. The patients revealed almost a total lack of proprioception when blindfolded. They stumbled and fell while walking and could not determine which way their joints were moving without looking. In addition, both failed to successfully move a finger from their noses to a target. The absence of certain sensory abilities is also astonishing - both patients could not feel the vibrations of a tuning fork pressed against their skin, could not differentiate between ends of a caliper pressed against their palms, and could not sense a soft brush across their palms and bottom of their feet. Furthermore, when this same soft brush was swept across hairy skin, both of the patients claimed that the sensation was prickly. This particular result revealed that the subjects were generally missing brain activation in the region linked to physical sensation, yet they appeared to have an emotional response to the brushing across hairy skin; these specific brain patterns directly contrasted with those of the control group participants. Additional tests performed on the two women revealed that the patients’ detection of pain, itching, and temperature was normal when compared to the control group findings, and that they possessed nervous system capabilities and cognitive functions appropriate for their ages.1
Because the patients are still able to function in daily life, it is apparent that the nervous system has alternate pathways that allow them to use sight to largely compensate for their lack of proprioception.3,4 Through further research, scientists can tap into these alternate pathways when designing therapies for similar patients. Additionally, the common physical features of both patients shed light on the fact that PIEZO2 gene mutations could contribute to the observed genetic musculoskeletal disorders.3 This suggests that proprioception itself is necessary for normal musculoskeletal development; it is possible that abnormalities developed over time as a result of patients’ postural responses and compensations to their deficiencies.4
In an era when our lives depend so heavily on our abilities to maneuver our bodies and coordinate movements, the idea of lacking proprioception is especially concerning. Bönnermann and Chesler’s discoveries open new doors for further investigation of PIEZO2’s role in the nervous system and musculoskeletal development. These discoveries can also aid in better understanding a variety of other neurological disorders. But, there is still much unknown about the full effects of the PIEZO2 mutation. For example, we do not know if musculoskeletal abnormalities injure the spinal cord, if the gene mutation poses additional consequences for the elderly, or if women are more susceptible to the disorder than are men. Furthermore, it is very likely that there are numerous other patients around the world who present similar symptoms to the 8-year-old girl and 18-year-old woman observed by Bönnermann and Chesler. While researchers work towards gaining a better understanding of the disease and developing specific therapies, these patients must focus on other coping mechanisms, such as reliance on vision, to accomplish even the most basic daily activities. Because contrary to popular perception, the sixth sense is not an ability to see ghosts; it is so much more.
- Chesler, A. T. et al. N Engl J Med. 2016, 375, 1355-1364
- Woo, S. et al. Nat Neurosci. 2015, 18, 1756-1762
- “‘Sixth sense’ may be more than just a feeling”. National Institutes of Health, https://www.nih.gov/news-events/news-releases/Sixth-sense-may-be-more-just-feeling (accessed Sept. 22, 2016).
- Price, Michael. “Researchers discover gene behind ‘sixth sense’ in humans”. Science Magazine, http://www.sciencemag.org/news/2016/09/researchers-discover-gene-behind-sixth-sense-humans (accessed Sept. 22, 2016)