1. Neuroscience

Gain of channel function and modified gating properties in TRPM3 mutants causing intellectual disability and epilepsy

  1. Evelien Van Hoeymissen
  2. Katharina Held
  3. Ana Cristina Nogueira Freitas
  4. Annelies Janssens
  5. Thomas Voets  Is a corresponding author
  6. Joris Vriens  Is a corresponding author
  1. KU Leuven, Belgium
https://doi.org/10.7554/eLife.57190
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Cite this article
  1. Evelien Van Hoeymissen
  2. Katharina Held
  3. Ana Cristina Nogueira Freitas
  4. Annelies Janssens
  5. Thomas Voets
  6. Joris Vriens
(2020)
Gain of channel function and modified gating properties in TRPM3 mutants causing intellectual disability and epilepsy
eLife 9:e57190.
https://doi.org/10.7554/eLife.57190
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Abstract

Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of disorders characterized by epilepsy with comorbid intellectual disability. Recently, two de novo heterozygous mutations in the gene encoding TRPM3, a calcium permeable ion channel, were identified as the cause of DEE in eight probands, but the functional consequences of the mutations remained elusive. Here we demonstrate that both mutations (V990M and P1090Q) have distinct effects on TRPM3 gating, including increased basal activity, higher sensitivity to stimulation by the endogenous neurosteroid pregnenolone sulphate (PS) and heat, and altered response to ligand modulation. Most strikingly, the V990M mutation affected the gating of the non-canonical pore of TRPM3, resulting in large inward cation currents via the voltage sensor domain in response to PS stimulation. Taken together, these data indicate that the two DEE mutations in TRPM3 result in a profound gain of channel function, which may lie at the basis of epileptic activity and neurodevelopmental symptoms in the patients.

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All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Evelien Van Hoeymissen

    Department of Development and Regeneration, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3897-8998

  2. Katharina Held

    Department of Development and Regeneration, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1727-9517

  3. Ana Cristina Nogueira Freitas

    VIB-KU Leuven Center for Brain and Disease Research, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.

  4. Annelies Janssens

    VIB-KU Leuven Center for Brain and Disease Research, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.

  5. Thomas Voets

    Laboratory of Ion Channel Research (LICR), VIB-KU Leuven Centre for Brain & Disease Research and Department of Cellular and Molecular Medicine, KU Leuven, KU Leuven, Leuven, Belgium
    For correspondence
    thomas.voets@kuleuven.vib.be
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5526-5821

  6. Joris Vriens

    Department of Development and Regeneration, KU Leuven, Leuven, Belgium
    For correspondence
    Joris.Vriens@kuleuven.be
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2502-0409

Funding

Fonds Wetenschappelijk Onderzoek (G.084515N)

  • Joris Vriens

Fonds Wetenschappelijk Onderzoek (G.0B1819N)

  • Joris Vriens

Fonds Wetenschappelijk Onderzoek (G.0565.07)

  • Thomas Voets
  • Joris Vriens

Fonds Wetenschappelijk Onderzoek (G.0825.11)

  • Thomas Voets
  • Joris Vriens

KU Leuven (C1-TRPLe)

  • Thomas Voets

Fonds Wetenschappelijk Onderzoek (POST DOC)

  • Katharina Held

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2020, Van Hoeymissen 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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  1. Evelien Van Hoeymissen
  2. Katharina Held
  3. Ana Cristina Nogueira Freitas
  4. Annelies Janssens
  5. Thomas Voets
  6. Joris Vriens
(2020)
Gain of channel function and modified gating properties in TRPM3 mutants causing intellectual disability and epilepsy
eLife 9:e57190.
https://doi.org/10.7554/eLife.57190

Share this article

https://doi.org/10.7554/eLife.57190

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