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

Gain-of-function variants in the ion channel gene TRPM3 underlie a spectrum of neurodevelopmental disorders
Gain-of-function variants in the ion channel gene TRPM3 underlie a spectrum of neurodevelopmental disorders
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 devel opmental delay, intellectual disability, epilepsy, musculo-skeletal anomalies, and altered pain percep tion. 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
2050-084X
Burglen, Lydie
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van Hoeymissen, Evelien
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Qebibo, Leila
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Barth, Magalie
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Belnap, Newell
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Boschann, Felix
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Depienne, Christel
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De Clercq, Katrien
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Douglas, Andrew
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Fitzgerald, Mark P
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Foulds, Nicola
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Garel, Catherine
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Helbig, Ingo
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Held, Katharina
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Horn, Denise
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Janssens, Annelies
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Kaindl, Angela M
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Narayanan, Vinodh
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Prager, Christine
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Rupin-Mas, Mailys
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Afenjar, Alexandra
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Zhao, Siyuan
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Ramaekers, Vincent TH
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Ruggiero, Sarah M
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Thomas, Simon
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Valence, Stephanie
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Van Maldergem, Lionel
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Rohacs, Tibor
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Rodriguez, Diana
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Dyment, David
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Voets, Thomas
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Vriens, Joris
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Burglen, Lydie
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van Hoeymissen, Evelien
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Qebibo, Leila
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Barth, Magalie
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Belnap, Newell
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Boschann, Felix
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Depienne, Christel
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De Clercq, Katrien
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Douglas, Andrew
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Fitzgerald, Mark P
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Foulds, Nicola
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Garel, Catherine
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Helbig, Ingo
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Held, Katharina
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Horn, Denise
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Janssens, Annelies
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Kaindl, Angela M
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Narayanan, Vinodh
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Prager, Christine
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Rupin-Mas, Mailys
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Afenjar, Alexandra
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Zhao, Siyuan
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Ramaekers, Vincent TH
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Ruggiero, Sarah M
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Thomas, Simon
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Valence, Stephanie
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Van Maldergem, Lionel
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Rohacs, Tibor
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Rodriguez, Diana
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Dyment, David
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Voets, Thomas
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Vriens, Joris
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Burglen, Lydie, van Hoeymissen, Evelien, Qebibo, Leila, Barth, Magalie, Belnap, Newell, Boschann, Felix, Depienne, Christel, De Clercq, Katrien, Douglas, Andrew, Fitzgerald, Mark P, Foulds, Nicola, Garel, Catherine, Helbig, Ingo, Held, Katharina, Horn, Denise, Janssens, Annelies, Kaindl, Angela M, Narayanan, Vinodh, Prager, Christine, Rupin-Mas, Mailys, Afenjar, Alexandra, Zhao, Siyuan, Ramaekers, Vincent TH, Ruggiero, Sarah M, Thomas, Simon, Valence, Stephanie, Van Maldergem, Lionel, Rohacs, Tibor, Rodriguez, Diana, Dyment, David, Voets, Thomas and Vriens, Joris (2023) Gain-of-function variants in the ion channel gene TRPM3 underlie a spectrum of neurodevelopmental disorders. eLife, 12, [e81032]. (doi:10.7554/eLife.81032).

Record type: Article

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 devel opmental delay, intellectual disability, epilepsy, musculo-skeletal anomalies, and altered pain percep tion. 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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Accepted/In Press date: 7 December 2022
Published date: 17 January 2023
Additional Information: Funding Information: We thank all parents and children for their willingness to participate to this study. We thank all members of the Laboratory of Endometrium, Endometriosis and Reproductive Medicine (LEERM) and the members of the Laboratory of Ion Channel Research (LICR) Leuven for their help during experiments and useful discussions. We thank Dr. L Gaspers for the kind gift on GCaMP6, and Bahar Bazeli for help with visualizing the TRPM3 variants on the cryo-EM structure. The study was supported by the Einstein Stiftung Fellowship through the Günter Endres Fond. We thank the Research Foundation-Flanders FWO, (G.0D1417N, G.084515N, G.0A6719N), the Research Council of the KU Leuven (C14/18/106, C3/21/049) for funding the project of JV, Einstein Stiftung for AMK, and the association “Connaître les syndromes cérébelleux” for funding the project of LB. EVH is a fellow of the Research Foundation-Flanders FWO (11E782N). Funding Information: We thank all parents and children for their willingness to participate to this study. We thank all members of the Laboratory of Endometrium, Endometriosis and Reproductive Medicine (LEERM) and the members of the Laboratory of Ion Channel Research (LICR) Leuven for their help during experiments and useful discussions. We thank Dr. L Gaspers for the kind gift on GCaMP6, and Bahar Bazeli for help with visualizing the TRPM3 variants on the cryo-EM structure. The study was supported by the Einstein Stiftung Fellowship through the Günter Endres Fond. Funding Information: We thank the Research Foundation-Flanders FWO, (G.0D1417N, G.084515N, G.0A6719N), the Research Council of the KU Leuven (C14/18/106, C3/21/049) for funding the project of JV, Einstein Stiftung for AMK, and the association “Connaître les syndromes cérébelleux” for funding the project of LB. EVH is a fellow of the Research Foundation-Flanders FWO (11E782N). Publisher Copyright: © Burglen, Van Hoeymissen et al.
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Identifiers

Local EPrints ID: 474631
URI: http://eprints.soton.ac.uk/id/eprint/474631
DOI: doi:10.7554/eLife.81032
ISSN: 2050-084X
PURE UUID: e8f22fe7-e294-45e2-9134-443f7751c523
ORCID for Andrew Douglas: ORCID iD orcid.org/0000-0001-5154-6714

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Date deposited: 28 Feb 2023 17:37
Last modified: 06 Jun 2024 01:48

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Contributors

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

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