Gain-of-function variants in the ion channel gene TRPM3 underlie a spectrum of neurodevelopmental disorders
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.
-
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
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.
Metrics
-
- 3,533
- views
-
- 554
- downloads
-
- 20
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Cell Biology
- Genetics and Genomics
A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve = 0.579), they offered marginal prediction improvement in PRS-only-based models (p=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites—lactate (p=8.8E-12), pyruvate (p=1.9E-10), and citrate (p=0.02)—linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (Pinteraction = 0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratiohighest vs. lowest total resilience metabolite quartile=0.71, 95% Confidence Interval = 0.64–0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (p=0.002) and optic nerve damage (p<0.0003) in Lmx1bV265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.
-
- Cell Biology
- Immunology and Inflammation
Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.