An inherited hypomorphic variant in PIEZO2 reveals structural features of mechanotransduction.
TL;DR
By explaining how a single amino acid change produces a hypomorphic PIEZO2 allele, the findings broaden the clinical spectrum of PIEZO2 disorders and offer structural insight into mechanotransduction.
Abstract
PIEZO2 is the principal mechanosensory channel for proprioception, touch, and many interoceptive processes, yet key details of how PIEZO channels convert force into electrochemical signals remain unclear. Here, we report fraternal twins with proprioceptive ataxia and scoliosis who carry an unreported PIEZO2 missense variant (N2434K) in compound heterozygosity with a null variant. Gene-edited mice confirm that N2434K is disease-causing, with in vivo recordings demonstrating deficits in sensory neuron mechanical responses. Despite normal membrane expression, the variant has severely reduced mechanically evoked current, which is suggestive of defective gating. N2434 is conserved between PIEZO1 and PIEZO2 and resides in the cap-pore linker, which bridges the extracellular cap and ion-conducting pore. Computational modeling, site-directed mutagenesis, and single-molecule imaging reveal that this region is essential for channel-wide conformational changes during gating. By explaining how a single amino acid change produces a hypomorphic PIEZO2 allele, our findings broaden the clinical spectrum of PIEZO2 disorders and offer structural insight into mechanotransduction.
