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While most disease-associated<jats:italic>SCN10A<\/jats:italic>variants confer gain-of-function properties to Na<jats:sub>V<\/jats:sub>1.8, resulting in hyperexcitability of sensory neurons, a few affect afferent excitability through a loss-of-function mechanism. Using whole-exome sequencing, we here identify a rare heterozygous<jats:italic>SCN10A<\/jats:italic>missense variant resulting in alteration p.V1287I in Na<jats:sub>V<\/jats:sub>1.8 in a patient with a 15-year history of progressively worsening temperature dysregulation in the distal extremities, particularly in the feet. Further symptoms include increasingly intensifying tingling and numbness in the fingers and increased sweating. To assess the impact of p.V1287I on channel function, we performed voltage-clamp recordings demonstrating that the alteration confers loss- and gain-of-function characteristics to Na<jats:sub>V<\/jats:sub>1.8 characterized by a right-shifted voltage dependence of channel activation and inactivation. Current-clamp recordings from transfected mouse dorsal root ganglion neurons further revealed that Na<jats:sub>V<\/jats:sub>1.8-V1287I channels broaden the action potentials of sensory neurons and increase their firing rates in response to depolarizing current stimulations, indicating a gain-of-function mechanism of the variant at the cellular level in a heterozygous setting. The data support the hypothesis that the properties of Na<jats:sub>V<\/jats:sub>1.8 p.V1287I are causative for the patient\u2019s symptoms and that nonpainful peripheral paresthesias should be considered part of the clinical spectrum of Na<jats:sub>V<\/jats:sub>1.8-associated disorders.<\/jats:p>","DOI":"10.1007\/s00424-023-02856-2","type":"journal-article","created":{"date-parts":[[2023,9,11]],"date-time":"2023-09-11T07:02:38Z","timestamp":1694415758000},"page":"1343-1355","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Peripheral temperature dysregulation associated with functionally altered NaV1.8 channels"],"prefix":"10.1007","volume":"475","author":[{"given":"Simon","family":"Loose","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Lischka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Kuehs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Nau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan H.","family":"Heinemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo","family":"Kurth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7666-460X","authenticated-orcid":false,"given":"Enrico","family":"Leipold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,9,11]]},"reference":[{"key":"2856_CR1","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1038\/379257a0","volume":"379","author":"AN Akopian","year":"1996","unstructured":"Akopian AN, Sivilotti L, Wood JN (1996) A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. 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