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

Elife. 2023 Jan 17:12:e81032. doi: 10.7554/eLife.81032.

Lydie Burglen ^# ¹ ², Evelien Van Hoeymissen ^# ³ ⁴ ⁵, Leila Qebibo ¹, Magalie Barth ⁶, Newell Belnap ⁷, Felix Boschann ⁸, Christel Depienne ⁹, Katrien De Clercq ³ ⁴ ⁵, Andrew G L Douglas ¹⁰, Mark P Fitzgerald ¹¹, Nicola Foulds ¹², Catherine Garel ¹ ¹³, Ingo Helbig ¹¹, Katharina Held ³ ⁴ ⁵, Denise Horn ⁸, Annelies Janssen ³ ⁴, Angela M Kaindl ¹⁴ ¹⁵ ¹⁶, Vinodh Narayanan ⁷, Christina Prager ¹⁵ ¹⁶, Mailys Rupin-Mas ¹⁷, Alexandra Afenjar ¹, Siyuan Zhao ¹⁸, Vincent Th Ramaekers ¹⁹, Sarah M Ruggiero ¹¹, Simon Thomas ²⁰, Stéphanie Valence ¹ ²¹, Lionel Van Maldergem ²² ²³, Tibor Rohacs ¹⁸, Diana Rodriguez ¹ ²¹, David Dyment ²⁴, Thomas Voets ³ ⁴, Joris Vriens ⁵

Affiliations

1 Centre de référence des malformations et maladies congénitales du cervelet, Départementde Génétique, APHP, Sorbonne University, Paris, France.
2 Developmental Brain Disorders Laboratory, Imagine Institute, Paris, France.
3 Laboratory of Ion Channel Research, Department of cellular and molecular medicine, University of Leuven, Leuven, Belgium.
4 VIB Center for Brain & Disease Research, Leuven, Belgium.
5 Laboratory of Endometrium, Endometriosis & Reproductive Medicine, Department Development & Regeneration, University of Leuven, Leuven, Belgium.
6 Department of Genetics, University Hospital of Angers, Angers, France.
7 Translational Genomics Research Institute (TGen), Neurogenomics Division, Center for Rare Childhood Disorders, Phoenix, United States.
8 Charité - Universitäts medizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Genetics and Human Genetics, Berlin, Germany.
9 Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
10 University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
11 Children's Hospital of Philadelphia, Philadelphia, United States.
12 Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
13 Service de Radiologie Pédiatrique, Hôpital Armand-Trousseau, Médecine Sorbonne Université, Paris, France.
14 Institute of Cell Biology and Neurobiology, Charité - Universitäts medizin Berlin, Berlin, Germany.
15 Department of Pediatric Neurology, Charité - Universitäts medizin Berlin, Berlin, Germany.
16 Charité - Universitäts medizin Berlin, Center for Chronically Sick Children, Berlin, Germany.
17 Department of Neuropediatrics, University Hospital of Angers, Angers, France.
18 Department of Pharmacology, Physiology and Neuroscience, Rutgers, The State University of New Jersey, Newark, United States.
19 Division Neuropediatrics, University Hospital Liège, Liège, Belgium.
20 Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, United Kingdom.
21 Sorbonne Université, Service de Neuropédiatrie, Hôpital Trousseau AP-HP, Paris, France.
22 Centre de Génétique Humaine, Université de Franche-Comté Besançon, Besancon, France.
23 Center of Clinical Investigation 1431, National Institute of Health and Medical Research, Besancon, France.
24 Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
# Contributed equally.

PMID: 36648066 DOI: 10.7554/eLife.81032

Abstract

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.

Keywords

TRPM3; cell biology; cerebellar atrophy; epilepsy; gain-of-function; human; intellectual disability; neurodevelopment; neuroscience.

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