A neurocutaneous Na V 1.8 channelopathy underlies a genetic subtype of primary idiopathic hyperhidrosis
- Suguru Yamauchi
- Jolien Vander Cruyssen
- Michele Cervellera
- Elizabeth Wohler
- Jolien De Waele
- Maxime Lammens
- Corinne Boehm
- Nara L Sobreira
- Carley Blevins
- Kaitlyn Ecoff
- Yuping Mei
- Margaux Theys
- Ife Shoyombo
- Maria Shishikura
- Hongrui Yi
- Kristen Rodgers
- Beverly Lee
- Hamza Khan
- Andrei Gurau
- Wasay Nizam
- Shivani Shirodkar
- Christine Kim
- Joshua Choi
- Daniel Coleman
- Brooke Dorman
- Takumi Iwasawa
- Jin U Kang
- Yves Heremans
- Hajime Orita
- Tetsu Fukunaga
- Filip Van Petegem
- Stephen B. Baylin
- Andreas S Barth
- Tae Hwan Chung
- Peter C Rowe
- Glenn Treisman
- Jinny Ha
- Ruslan I Dmitriev
- David Valle
- Frank Bosmans
- Malcolm V Brock
2026-07-17
Primary idiopathic hyperhidrosis (PIH) is a poorly understood disorder characterized by excessive sweating. We identify a genetically defined subset of PIH associated with rare coding changes in voltage-gated Na + (Na V ) channels. Whole-exome sequencing of hereditary PIH families revealed gene-level enrichment within the Na V channel family, with SCN10A (Na V 1.8) most strongly implicated. A knock-in mouse carrying the clinically observed Na V 1.8 p.R14L substitution recapitulated excessive sweating. Na V 1.8 was detected in a subset of postganglionic neurons in thoracic sympathetic ganglia in humans and mice, where p.R14L produced a gain-of-function profile that enhanced cholinergic responsiveness. Excessive sweating in mutant mice was reversible with Na V channel inhibition, including clinically used agents and a Na V 1.8-preferential compound. Together, these findings define a targetable neurocutaneous channelopathy underlying a subset of PIH and support a model in which excessive sweating arises from either gland-intrinsic dysfunction or altered sympathetic drive, motivating stratified therapeutic approaches.