eLife (Jan 2023)

Gain-of-function variants in the ion channel gene TRPM3 underlie a spectrum of neurodevelopmental disorders

  • Lydie Burglen,
  • Evelien Van Hoeymissen,
  • Leila Qebibo,
  • Magalie Barth,
  • Newell Belnap,
  • Felix Boschann,
  • Christel Depienne,
  • Katrien De Clercq,
  • Andrew GL Douglas,
  • Mark P Fitzgerald,
  • Nicola Foulds,
  • Catherine Garel,
  • Ingo Helbig,
  • Katharina Held,
  • Denise Horn,
  • Annelies Janssen,
  • Angela M Kaindl,
  • Vinodh Narayanan,
  • Christina Prager,
  • Mailys Rupin-Mas,
  • Alexandra Afenjar,
  • Siyuan Zhao,
  • Vincent Th Ramaekers,
  • Sarah M Ruggiero,
  • Simon Thomas,
  • Stéphanie Valence,
  • Lionel Van Maldergem,
  • Tibor Rohacs,
  • Diana Rodriguez,
  • David Dyment,
  • Thomas Voets,
  • Joris Vriens

DOI
https://doi.org/10.7554/eLife.81032
Journal volume & issue
Vol. 12

Abstract

Read online

TRPM3 is a temperature- and neurosteroid-sensitive plasma membrane cation channel expressed in a variety of neuronal and non-neuronal cells. Recently, rare de novo variants in TRPM3 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 TRPM3 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.

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