A neurocutaneous Na_V1.8 channelopathy underlies a genetic subtype of primary idiopathic hyperhidrosis.

Authors

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

Published in

Science advances. Volume 12. Issue 29. Pages eaed3221. Jul 17, 2026. Epub Jul 17, 2026.

Abstract

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_V1.8) most strongly implicated. A knock-in mouse carrying the clinically observed Na_V1.8^p.R14L substitution recapitulated excessive sweating. Na_V1.8 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_V1.8-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.

PMID:
42467787
Bibliographic data and abstract were imported from PubMed on 18 Jul 2026.

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