Gene Governing Senses of Touch and Body Position Discovered

Megan Brooks

September 22, 2016

Scientists have discovered that the PIEZO2 gene plays a key role in human touch and proprioception, with the help of two patients with a unique neurologic disorder that remains unclassified.

Proprioception — the awareness of the position of one's own body — is a crucial component of the motor control system, and loss of proprioception leads to deficits in motor function. The sense of proprioception is disturbed in many neurologic disorders.

"Our study highlights the critical importance of PIEZO2 and the senses it controls in our daily lives," Carsten G. Bönnemann, MD, senior investigator at the National Institute of Neurological Disorders and Stroke (NINDS) and a co-leader of the study, said in a statement.

"The results establish that PIEZO2 is a touch and proprioception gene in humans. Understanding its role in these senses may provide clues to a variety of neurological disorders," Dr Bönnemann added.

The research was published online September 21 in New England Journal of Medicine (NEJM).

Loss of PIEZO2 Function, Loss of Touch, Perception

Prior studies in mice have shown that PIEZO2 is essential for a variety of mechanosensory responses, including aspects of touch and proprioception. Prior studies have found that mutations in the PIEZO2 gene may contribute to genetic musculoskeletal disorders, including distal arthrogryposis type 5, Gordon's syndrome, and Marden-Walker syndrome.

The two patients described in the NEJM article have inactivating (loss of function) variants in the PIEZO2 gene that block the normal activity of the PIEZO2 protein. One is a girl age 9 years and the other is a young woman age 19 years. They are not related to each other.

"Clinically, we observed general losses in vibration detection, touch discrimination (specifically on glabrous skin), and joint proprioception. We conclude that PIEZO2 is required to transduce the mechanical forces at the sensory afferent terminals in these various contexts in humans," the authors write.

"When I first examined the patients, particularly the older patient, it was clear that this was something I had not seen before and what struck me the most was the proprioception [deficits]," Dr Bönnemann noted in an interview with Medscape Medical News.

"Whether I moved her shoulder or wrist or finger, it didn't make a difference. She was just guessing where it was going. And she also had lost her vibration sense, so when I put a vibrating tuning fork on part of her body, anywhere I placed it, she was not able to perceive it properly. The younger patient has a similar syndrome."

The patients could, however, feel gentle mechanical stimulation (stroking or brushing) of hairy skin. "This is another interesting facet of the story, Alexander T. Chesler, PhD, investigator at the National Institutes of Health's National Center for Complementary and Integrative Health (NCCIH), and first author of the paper, told Medscape Medical News.

"If you brush the palms of their hands, they can't feel it at all," Dr Chesler said. "But if you brush their forearm, they can feel it. This gives us insight into the complexity of touch but also that there are really distinct channels that we have in our nervous system that are detecting specific features of touch that this helps us delineate."

Test for PIEZO2 in Idiopathic Scoliosis?

"Remarkably," the patients are still able to perform complex movements by relying on compensatory inputs, such as vision, the authors report.

"These two patients have an inability to sense types of touch and a complete loss of proprioception. These patients have many fine motor deficits and that impacts their daily lives, including eating and dressing and walking, yet they have come up with a variety of fascinating compensatory mechanisms using their other senses of vision and hearing to compensate for the inability to have proprioception," Dr Chesler commented.

Both patients also have movement and balance problems, hip and finger deformities, and a type of progressive scoliosis that does not conform to standard diagnostic classification.

"In addition to their loss of proprioception, their inability to sense their body position and regulate their musculature has led to things like idiopathic scoliosis and joint contractures and bone malformations. Perhaps there are polymorphisms in this gene" related to idiopathic scoliosis, Dr Chesler said.

Dr Bönnemann told Medscape Medical News it might be "worthwhile" testing for this gene mutation in idiopathic scoliosis.

It's also interesting, say the researchers, that despite the neuromuscular, skeletal, and sensory deficits, the patients' nervous systems appear to be developing normally, as the patients were able to feel pain, itch, and temperature normally.

"What's remarkable about these patients is how much their nervous systems compensate for their lack of touch and body awareness," Dr Bönnemann said in the statement. "It suggests the nervous system may have several alternate pathways that we can tap into when designing new therapies."

The neurologic affliction or syndrome in the two patients remains unnamed.

This research was supported by the NCCIH and NINDS intramural research programs.

N Engl J Med. Published online September 21, 2016. Abstract

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