Gain-of-function variants in the ion channel gene TRPM3 underlie a spectrum of neurodevelopmental disorders
- INSERM UMR 1163, France
- KU Leuven, Belgium
- Hôpitaux Universitaires Paris-Ouest, France
- Centre Hospitalier Universitaire d'Angers, France
- Translational Genomics Research Institute, United States
- Charité - Universitäts medizin Berlin, Germany
- Essen University Hospital, United States
- University Hospital Southampton NHS Foundation Trust, United Kingdom
- Children's Hospital of Philadelphia, United States
- Charité - Universitätsmedizin Berlin, Germany
- Rutgers, The State University of New Jersey, United States
- University of Liège, Belgium
- Salisbury District Hospital, United Kingdom
- Centre Hospitalier Universitaire de Besançon, France
- University of Ottawa, Canada
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 (DEE), 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 (Van Hoeymissen et al., 2020; Zhao et al., 2020). Here, we report a further ten 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 sulphate, 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.
Data availability
Raw data for the following figures are made available via figshare (https://doi.org/10.6084/m9.figshare.21799604): Figure 1 - Figure Supplement 1; Figure 3; Figure 3 - Figure Supplement 1, 2, 3 and 4; Figure 4; Figure 4 - Figure Supplement 1, 2 and 3.
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Data of Evelien Van Hoeymissen for manuscript "Gain-of-function variants in the ion channel gene TRPM3 underlie a spectrum of neurodevelopmental disorders"https://doi.org/10.6084/m9.figshare.21799604.
Article and author information
Author details
Evelien Van Hoeymissen
Funding
Flanders' FOOD (G.0D1417N)
- Joris Vriens
Flanders' FOOD (G.084515N)
- Joris Vriens
Flanders' FOOD (G.0A6719N)
- Joris Vriens
Flanders' FOOD (11E782)
- Evelien Van Hoeymissen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The study was performed in accordance with the guidelines specified by the institutional review boards and ethics committees at each institution. Information of institutional protocols are provided in the section of Material & Methods. All parents agreed on sharing and publicing the patients' information.Patients information:patient 1, 3, 4, 7: Written informed consent was obtained from the parents of the probands for molecular genetic analysis and possible publication of the anonymized clinical data. The study was done in accordance with local research and ethics requirements.patient 2: Parents signed an informed consent, received a genetic counselling before and after the analysis, and the genetic study was performed in accordance with German and French ethical requirements and laws.patient 5: UK ethical approval by the Cambridge South Research Ethics Committee (10/H0305/83)patient 6: outine clinical care within the UK National Health Service, and so no specific institutional ethical approval was requiredpatient 8: Declaration of Helsinki with local approval by the Children's Hospital of Philadelphia (CHOP) Institutional Review Board (IRB 15-12226).patient 9: The participating family signed the IRB research protocol of the University of Pennsylvania division of Neurologypatient 10: The study protocol and consent documents were approved by the Western Institutional Review Board (WIRB # 20120789). The retrospective analysis of epilepsy patient data was approved by the local ethics committees of the Charité (approval no. EA2/084/18)
Copyright
© 2023, Burglen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Gain-of-function variants in the ion channel gene TRPM3 underlie a spectrum of neurodevelopmental disorders
eLife 12:e81032.
https://doi.org/10.7554/eLife.81032
