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.).