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
Affiliations
- Lydie Burglen
- Centre de référence des malformations et maladies congénitales du cervelet, Départementde Génétique, APHP, Sorbonne University, Paris, France; Developmental Brain Disorders Laboratory, Imagine Institute, Paris, France
- Evelien Van Hoeymissen
- ORCiD
- Laboratory of Ion Channel Research, Department of cellular and molecular medicine, University of Leuven, Leuven, Belgium; VIB Center for Brain & Disease Research, Leuven, Belgium; Laboratory of Endometrium, Endometriosis & Reproductive Medicine, Department Development & Regeneration, University of Leuven, Leuven, Belgium
- Leila Qebibo
- Centre de référence des malformations et maladies congénitales du cervelet, Départementde Génétique, APHP, Sorbonne University, Paris, France
- Magalie Barth
- Department of Genetics, University Hospital of Angers, Angers, France
- Newell Belnap
- Translational Genomics Research Institute (TGen), Neurogenomics Division, Center for Rare Childhood Disorders, Phoenix, United States
- Felix Boschann
- Charité – Universitäts medizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Genetics and Human Genetics, Berlin, Germany
- Christel Depienne
- Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany
- Katrien De Clercq
- Laboratory of Ion Channel Research, Department of cellular and molecular medicine, University of Leuven, Leuven, Belgium; VIB Center for Brain & Disease Research, Leuven, Belgium; Laboratory of Endometrium, Endometriosis & Reproductive Medicine, Department Development & Regeneration, University of Leuven, Leuven, Belgium
- Andrew GL Douglas
- University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
- Mark P Fitzgerald
- Children's Hospital of Philadelphia, Philadelphia, United States
- Nicola Foulds
- Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
- Catherine Garel
- Centre de référence des malformations et maladies congénitales du cervelet, Départementde Génétique, APHP, Sorbonne University, Paris, France; Service de Radiologie Pédiatrique, Hôpital Armand-Trousseau, Médecine Sorbonne Université, Paris, France
- Ingo Helbig
- Children's Hospital of Philadelphia, Philadelphia, United States
- Katharina Held
- Laboratory of Ion Channel Research, Department of cellular and molecular medicine, University of Leuven, Leuven, Belgium; VIB Center for Brain & Disease Research, Leuven, Belgium; Laboratory of Endometrium, Endometriosis & Reproductive Medicine, Department Development & Regeneration, University of Leuven, Leuven, Belgium
- Denise Horn
- ORCiD
- Charité – Universitäts medizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Genetics and Human Genetics, Berlin, Germany
- Annelies Janssen
- ORCiD
- Laboratory of Ion Channel Research, Department of cellular and molecular medicine, University of Leuven, Leuven, Belgium; VIB Center for Brain & Disease Research, Leuven, Belgium
- Angela M Kaindl
- ORCiD
- Institute of Cell Biology and Neurobiology, Charité - Universitäts medizin Berlin, Berlin, Germany; Department of Pediatric Neurology, Charité - Universitäts medizin Berlin, Berlin, Germany; Charité – Universitäts medizin Berlin, Center for Chronically Sick Children, Berlin, Germany
- Vinodh Narayanan
- ORCiD
- Translational Genomics Research Institute (TGen), Neurogenomics Division, Center for Rare Childhood Disorders, Phoenix, United States
- Christina Prager
- Department of Pediatric Neurology, Charité - Universitäts medizin Berlin, Berlin, Germany; Charité – Universitäts medizin Berlin, Center for Chronically Sick Children, Berlin, Germany
- Mailys Rupin-Mas
- Department of Neuropediatrics, University Hospital of Angers, Angers, France
- Alexandra Afenjar
- Centre de référence des malformations et maladies congénitales du cervelet, Départementde Génétique, APHP, Sorbonne University, Paris, France
- Siyuan Zhao
- ORCiD
- Department of Pharmacology, Physiology and Neuroscience, Rutgers, The State University of New Jersey, Newark, United States
- Vincent Th Ramaekers
- Division Neuropediatrics, University Hospital Liège, Liège, Belgium
- Sarah M Ruggiero
- Children's Hospital of Philadelphia, Philadelphia, United States
- Simon Thomas
- Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, United Kingdom
- Stéphanie Valence
- Centre de référence des malformations et maladies congénitales du cervelet, Départementde Génétique, APHP, Sorbonne University, Paris, France; Sorbonne Université, Service de Neuropédiatrie, Hôpital Trousseau AP-HP, Paris, France
- Lionel Van Maldergem
- Centre de Génétique Humaine, Université de Franche-Comté Besançon, Besancon, France; Center of Clinical Investigation 1431, National Institute of Health and Medical Research, Besancon, France
- Tibor Rohacs
- ORCiD
- Department of Pharmacology, Physiology and Neuroscience, Rutgers, The State University of New Jersey, Newark, United States
- Diana Rodriguez
- Centre de référence des malformations et maladies congénitales du cervelet, Départementde Génétique, APHP, Sorbonne University, Paris, France; Sorbonne Université, Service de Neuropédiatrie, Hôpital Trousseau AP-HP, Paris, France
- David Dyment
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada
- Thomas Voets
- Laboratory of Ion Channel Research, Department of cellular and molecular medicine, University of Leuven, Leuven, Belgium; VIB Center for Brain & Disease Research, Leuven, Belgium
- Joris Vriens
- ORCiD
- Laboratory of Endometrium, Endometriosis & Reproductive Medicine, Department Development & Regeneration, University of Leuven, Leuven, Belgium
- DOI
- https://doi.org/10.7554/eLife.81032
- Journal volume & issue
-
Vol. 12
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