Our somatosensory system detects mechanical stimuli with exquisite sensitivity. We can feel the movement a single hair, discriminate two points on our fingertips with sub-millimeter accuracy, and differentiate changes in vibrational amplitude and frequency over several orders of magnitude. Additionally, our proprioceptors create a dynamic map of our bodies in space through vigilant monitoring of our muscles and tendons. My lab has been focusing on increasing our understanding of the distinct subtypes of mechanosensory neurons that exist, the molecular architecture underlying force transduction, and the physiological roles these molecules and cells play in touch and pain. Mechanosensitive ion channels are key transducers of membrane tension, converting force into electrochemical signals. Piezo2 is one such molecule that is found in sensory neurons, skin, lung and bladder. Despite sharing Piezo2 as a common sensor, the tuning of cells within these tissues to mechanical stimuli can differ dramatically. The sensory neurons that innervate the skin exemplify such specificity in that they are exquisitely tuned to respond to either high or low threshold indentation, hair movement, or vibration. We have been using in vitro and in vivo systems to better understand the function of Piezo2 in mice, specifically determining how the gene is regulated within sensory neurons and delineating the specific roles it is playing in touch and pain. In recent years, great progress as been made researching model organisms. How well these studies translate to humans is an open question. The study of rare inherited conditions offers an alternative approach to gain a window into the genetic underpinnings of human physiology. As part of an ongoing screen of patients with undiagnosed neuromuscular disorders, we are collaborating with Carsten Bonmmann (NINDS) to study patients he has identified with profound but selective deficits in mechanosensation. We are combining exome sequencing, sensory testing, and functional imaging in humans with model systems studies in heterologous cell lines and mice. It is our hope that by doing so we will discovery new disease alleles while better understanding the basic biology that underlies mechanosensation.