The Role of PIEZO2 in Human Mechanosensation

Abstract

Background: The senses of touch and proprioception evoke a range of perceptions and rely on the ability to detect and transduce mechanical force. The molecular and neural mechanisms underlying these sensory functions remain poorly defined. The stretch-gated ion channel PIEZO2 has been shown to be essential for aspects of mechanosensation in model organisms.

Methods: We performed whole-exome sequencing analysis in two patients who had unique neuromuscular and skeletal symptoms, including progressive scoliosis, that did not conform to standard diagnostic classification. In vitro and messenger RNA assays, functional brain imaging, and psychophysical and kinematic tests were used to establish the effect of the genetic variants on protein function and somatosensation.

Results: Each patient carried compound-inactivating variants in PIEZO2, and each had a selective loss of discriminative touch perception but nevertheless responded to specific types of gentle mechanical stimulation on hairy skin. The patients had profoundly decreased proprioception leading to ataxia and dysmetria that were markedly worse in the absence of visual cues. However, they had the ability to perform a range of tasks, such as walking, talking, and writing, that are considered to rely heavily on proprioception.

Conclusions: Our results show that PIEZO2 is a determinant of mechanosensation in humans. (Funded by the National Institutes of Health Intramural Research Program.).

Figures

Figure 1. Clinical and Genetic Characteristics of Patients with Null Variants in PIEZO2

In Panel A, photographs of the patients’ hands (left side) and radiographs of the patients’ spines (right side; obtained when Patient 1 was 16 years of age and Patient 2 was 9 years of age) show skeletal malformations. Panel B shows PIEZO2 variants and segregation results in unaffected family members. Patient 1 is compound heterozygous for a paternally inherited p.R1575* null variant (red) and a maternally inherited p.R1685* null variant (red). Patient 2 is compound heterozygous for a maternally inherited p.R1685* null variant (red) and a paternally inherited p.R1685P missense variant (pink). Wild-type alleles are shown in gray. Panel C shows quantification of the mechanically evoked currents recorded from a line of human embryonic kidney cells transfected with a wild-type mouse Piezo2 construct (from 15 cells), cells transfected with constructs carrying the R1575*, R1685P, and R1685* variants in Piezo2 (from 7, 11, and 7 cells, respectively), and sham cells transfected with green fluorescent protein (from 9 cells). I bars indicate standard errors. Panel D shows the results of reverse-transcriptase–polymerase-chain-reaction (RT-PCR) amplification of a fragment of PIEZO2 (788 base pairs, top) that spans all variants and was generated from total RNA from skin-biopsy specimens, as well as RT-PCR amplification of a control Merkel cell marker, ATOH1 (763 base pairs, bottom), generated from complementary DNA.

Figure 2. Results of Sensory Testing

Panel A shows the results of testing for punctate-touch detection, vibration detection, and two-point touch discrimination performed on glabrous skin, and Panel B shows the results of testing for punctate-touch detection and vibration detection performed on hairy skin. Panel C shows the thresholds of mechanical pain, including pinprick pain and pressure pain. Panel D shows the thresholds of thermal (cool and warm) detection and heat pain. Panel E shows the results of testing for the detection of slow brushing performed on hairy skin and on glabrous skin. For punctate-touch detection, mechanical pain, and thermal detection and pain, a higher threshold indicates lower sensitivity. I bars indicate standard deviations. P values are derived from the Crawford–Howell t-test and are not shown for comparisons that did not reach statistical significance (i.e., with P values >0.05).

Figure 3. Results of the Kinematic Reaching Task

During the kinematic reaching task, participants were instructed to use the dominant index finger to alternate between touching the nose and touching a target approximately 50 cm from the sternum while their eyes were either open or covered. Shown are two-dimensional projections mapping the trajectory of the finger during the skilled phase (when the finger was ≤15 cm from the target), as well as for the total path (which includes both the ballistic phase [when the finger was >15 cm from the target] and the skilled phase), for a control participant (Panel A), Patient 1 (Panel B), and Patient 2 (Panel C). Results of the task performed with eyes open are shown in gray, and results with eyes covered are shown in green (in the control participant) or magenta (in the patients). Also shown are graphs of the total path length with eyes open and eyes covered. (See Videos 3 through 6, available at NEJM.org.)