Journal article
An inherited hypomorphic variant in PIEZO2 reveals structural features of mechanotransduction
Neuron (Cambridge, Mass.)
08/24/2026
DOI: 10.1016/j.neuron.2026.07.030
PMID: 42636812
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.
Details
- Title: Subtitle
- An inherited hypomorphic variant in PIEZO2 reveals structural features of mechanotransduction
- Creators
- Alec R Nickolls - National Institutes of HealthEric M Mulhall - Scripps Institution of OceanographyDaniel J Orlin - National Institutes of HealthOleg Yarishkin - Scripps Institution of OceanographyLuis O Romero - The University of Texas Health Science CenterBriar Bell - The University of Texas Health Science CenterXin Hu - National Institutes of HealthCaitlin A Madden - National Institutes of HealthRaiza R Hardy - National Institutes of HealthGabrielle S O'Brien - National Center for Complementary and Integrative HealthSandra Donkervoort - National Institutes of HealthDimah N Saade - National Institutes of HealthTanya J Lehky - National Institutes of HealthA Reghan Foley - National Institute of Neurological Disorders and StrokeDiana X Bharucha-Goebel - National Institute of Neurological Disorders and StrokeJahannaz Dastgir - Regenxbio (United States)Valeria Vásquez - The University of Texas Health Science CenterJulio F Cordero-Morales - The University of Texas Health Science CenterCarsten G Bönnemann - National Institute of Neurological Disorders and StrokeArdem Patapoutian - Scripps Institution of OceanographyMelanie Falgairolle - National Center for Complementary and Integrative HealthAlexander T Chesler - National Center for Complementary and Integrative Health
- Resource Type
- Journal article
- Publication Details
- Neuron (Cambridge, Mass.)
- DOI
- 10.1016/j.neuron.2026.07.030
- PMID
- 42636812
- ISSN
- 0896-6273
- eISSN
- 1097-4199
- Publisher
- Elsevier
- Grant note
- R01 NS131184 / NINDS NIH HHS
- Language
- English
- Electronic publication date
- 08/24/2026
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9985220184102771
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