A neurocutaneous Na <sub>V</sub> 1.8 channelopathy underlies a genetic subtype of primary idiopathic hyperhidrosis
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.
Authors
- Kristen Rodgers (ORCID: https://orcid.org/0000-0003-4302-9578)
- Beverly Lee
- CD Boehm
- Malcolm Brock (ORCID: https://orcid.org/0000-0003-2961-851X)
- Tae Chung (ORCID: https://orcid.org/0000-0002-0270-5181)
- Andreas S. Barth (ORCID: https://orcid.org/0000-0001-5275-8049)
- Jolien De Waele (ORCID: https://orcid.org/0000-0003-0674-4521)
- Hongrui Yi
- Andrei Gurau (ORCID: https://orcid.org/0000-0003-4610-721X)
- Frank Bosmans (ORCID: https://orcid.org/0000-0002-0451-6050)
- David Valle (ORCID: https://orcid.org/0000-0002-6560-4281)
- Maria Shishikura (ORCID: https://orcid.org/0000-0002-7305-5358)
- Carley Blevins
- Takumi Iwasawa (ORCID: https://orcid.org/0009-0008-9278-6464)
- Jolien Vander Cruyssen
- Maxime Lammens (ORCID: https://orcid.org/0000-0002-2690-9955)
- Tetsu Fukunaga (ORCID: https://orcid.org/0000-0003-4802-8945)
- Stephen B. Baylin (ORCID: https://orcid.org/0000-0003-3697-3798)
- Hajime Orita (ORCID: https://orcid.org/0000-0002-8263-7069)
- Peter C. Rowe (ORCID: https://orcid.org/0000-0002-3586-2677)
- Nara Sobreira (ORCID: https://orcid.org/0000-0002-5228-5613)
- Ruslan I. Dmitriev (ORCID: https://orcid.org/0000-0002-0347-8718)
- Margaux Theys (ORCID: https://orcid.org/0000-0002-0058-104X)
- Wasay Nizam (ORCID: https://orcid.org/0000-0002-9095-1840)
- Yves Heremans (ORCID: https://orcid.org/0000-0002-2608-974X)
- Suguru Yamauchi (ORCID: https://orcid.org/0000-0001-5418-7112)
- Filip Van Petegem (ORCID: https://orcid.org/0000-0003-2728-8537)
- Joshua Choi (ORCID: https://orcid.org/0000-0001-5354-9695)
- Hamza Khan (ORCID: https://orcid.org/0000-0002-6553-5343)
- Jin U. Kang (ORCID: https://orcid.org/0000-0001-5817-1935)
- Yuping Mei
- Kaitlyn Ecoff
- Shivani Shirodkar (ORCID: https://orcid.org/0009-0008-4836-9583)
- IFE Shoyombo
- Christine Kim
- Michele Cervellera
- Glenn Treisman
- Elizabeth Wohler
- Jinny Ha
- Brooke Dorman
- Daniel Coleman
Institutions
- Deborah Heart and Lung Center (US)
- Allegheny Health Network (US)
- Vrije Universiteit Brussel (BE)
- University of British Columbia (CA)
- Johns Hopkins University (US)
- Toyo University (JP)
- Johns Hopkins Medicine (US)
- Ghent University (BE)
- Juntendo University (JP)
- Sidney Kimmel Cancer Center (US)
- Sidney Kimmel Comprehensive Cancer Center (US)
Publication Details
- Journal
- Science Advances
- Published
- 2026-07-17
- DOI
- https://doi.org/10.1126/sciadv.aed3221
- Primary Topic
- Sympathectomy and Hyperhidrosis Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Heart Association
- Dysautonomia Foundation
- Fonds Wetenschappelijk Onderzoek
- Vrije Universiteit Brussel
- Promotion and Mutual Aid Corporation for Private Schools of Japan
- National Institutes of Health
- HORIZON EUROPE Framework Programme
- National Cancer Institute
- Banks Family Foundation