• Alexander T Chesler, Marcin Szczot, Diana Bharucha-Goebel, Marta Čeko, Sandra Donkervoort, Claire Laubacher, Leslie H Hayes, Katharine Alter, Cristiane Zampieri, Christopher Stanley, A Micheil Innes, Jean K Mah, Carla M Grosmann, Nathaniel Bradley, David Nguyen, A Reghan Foley, Claire E Le Pichon, and Carsten G Bönnemann.
• From the National Center for Complementary and Integrative Health (A.T.C., M.S., M.C., C.L.), the National Institute of Neurological Disorders and Stroke (D.B.-G., S.D., L.H.H., N.B., D.N., A.R.F., C.E.L.P., C.G.B.), and the Functional and Applied Biomechanics Section, Rehabilitation Medicine Department, Clinical Center (K.A., C.Z., C.S.), National Institutes of Health, Bethesda, MD; the Division of Neurology, Children's National Health System, Washington, DC (D.B.-G.); the Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine (A.M.I.), and the Department of Clinical Neurosciences and Department of Pediatrics, Alberta Children's Hospital Research Institute (J.K.M.), University of Calgary, Calgary, Canada; and the Departments of Neurosciences and Pediatrics, School of Medicine, University of California, San Diego, Rady Children's Hospital, San Diego, CA (C.M.G.).
• N. Engl. J. Med. 2016 Oct 6; 375 (14): 1355-1364.

AbstractBackground 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.).

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