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

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.

Data availability

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.

Reviewing Editor

  1. Leon D Islas, Universidad Nacional Autónoma de México, Mexico

Version history

  1. Received: March 24, 2020
  2. Accepted: May 13, 2020
  3. Accepted Manuscript published: May 19, 2020 (version 1)
  4. Version of Record published: May 27, 2020 (version 2)
  5. Version of Record updated: September 30, 2020 (version 3)

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.

Metrics

  • 1,944
    Page views
  • 303
    Downloads
  • 29
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

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)

  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

Further reading

    1. Neuroscience
    Harry Clark, Matthew F Nolan
    Research Article

    Grid firing fields have been proposed as a neural substrate for spatial localisation in general or for path integration in particular. To distinguish these possibilities, we investigate firing of grid and non-grid cells in the mouse medial entorhinal cortex during a location memory task. We find that grid firing can either be anchored to the task environment, or can encode distance travelled independently of the task reference frame. Anchoring varied between and within sessions, while spatial firing of non-grid cells was either coherent with the grid population, or was stably anchored to the task environment. We took advantage of the variability in task-anchoring to evaluate whether and when encoding of location by grid cells might contribute to behaviour. We find that when reward location is indicated by a visual cue, performance is similar regardless of whether grid cells are task-anchored or not, arguing against a role for grid representations when location cues are available. By contrast, in the absence of the visual cue, performance was enhanced when grid cells were anchored to the task environment. Our results suggest that anchoring of grid cells to task reference frames selectively enhances performance when path integration is required.

    1. Neuroscience
    Kiwamu Kudo, Kamalini G Ranasinghe ... Srikantan S Nagarajan
    Research Article

    Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) to investigate the trajectories of long-range and local neural synchrony across AD stages, estimated from resting-state magnetoencephalography. The increases in neural synchrony in the delta-theta band and the decreases in the alpha and beta bands showed progressive changes throughout the stages of the EBM. Decreases in alpha and beta band synchrony preceded both neurodegeneration and cognitive decline, indicating that frequency-specific neuronal synchrony abnormalities are early manifestations of AD pathophysiology. The long-range synchrony effects were greater than the local synchrony, indicating a greater sensitivity of connectivity metrics involving multiple regions of the brain. These results demonstrate the evolution of functional neuronal deficits along the sequence of AD progression.