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Recently, rare de novo variants in\n                    <jats:italic>TRPM3<\/jats:italic>\n                    were identified in individuals with developmental and epileptic encephalopathy, but the link between TRPM3 activity and neuronal disease remains poorly understood. We previously reported that two disease-associated variants in TRPM3 lead to a gain of channel function . Here, we report a further 10 patients carrying one of seven additional heterozygous\n                    <jats:italic>TRPM3<\/jats:italic>\n                    missense variants. These patients present with a broad spectrum of neurodevelopmental symptoms, including global developmental delay, intellectual disability, epilepsy, musculo-skeletal anomalies, and altered pain perception. We describe a cerebellar phenotype with ataxia or severe hypotonia, nystagmus, and cerebellar atrophy in more than half of the patients. All disease-associated variants exhibited a robust gain-of-function phenotype, characterized by increased basal activity leading to cellular calcium overload and by enhanced responses to the neurosteroid ligand pregnenolone sulfate when co-expressed with wild-type TRPM3 in mammalian cells. The antiseizure medication primidone, a known TRPM3 antagonist, reduced the increased basal activity of all mutant channels. These findings establish gain-of-function of TRPM3 as the cause of a spectrum of autosomal dominant neurodevelopmental disorders with frequent cerebellar involvement in humans and provide support for the evaluation of TRPM3 antagonists as a potential therapy.\n                  <\/jats:p>","DOI":"10.7554\/elife.81032","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T10:15:12Z","timestamp":1673864112000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.81032","source":"Crossref","is-referenced-by-count":36,"title":["Gain-of-function variants in the ion channel gene TRPM3 underlie a spectrum of neurodevelopmental disorders"],"prefix":"10.7554","volume":"12","author":[{"given":"Lydie","family":"Burglen","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02en5vm52","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre de r\u00e9f\u00e9rence des malformations et maladies cong\u00e9nitales du cervelet, D\u00e9partementde 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