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Two pairs of CACNA1I (CaV3.3) variants with opposite effects on channel function cause neurodevelopmental disorders of varying severity.

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Related Experiment Video

Updated: Jun 3, 2025

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Autism-Linked Mutations in α2δ-1 and α2δ-3 Reduce Protein Membrane Expression but Affect Neither Calcium Channels nor

Sabrin Haddad1,2, Manuel Hessenberger1, Cornelia Ablinger1,2

  • 1Division of Physiology, Department of Pharmacology, Physiology, and Microbiology, Karl Landsteiner University of Health Sciences, 3500 Krems, Austria.

Pharmaceuticals (Basel, Switzerland)
|January 8, 2025
PubMed
Summary

Autism spectrum disorder (ASD) associated variants in α2δ-1 and α2δ-3 proteins do not affect channel function. These mutations may impact synapse formation or neuronal networks, not classical signaling pathways.

Keywords:
autism spectrum disorderauxiliary subunitcalcium currentcultured hippocampal neuronselectrophysiologytrans-synaptic functionvoltage-gated calcium channels

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Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • α2δ proteins (subunits of voltage-gated calcium channels) are crucial for neuronal development, including axonal wiring and synapse formation.
  • Rare variants in CACNA2D1 (α2δ-1) and CACNA2D3 (α2δ-3) genes are linked to autism spectrum disorder (ASD), but their pathogenicity and underlying mechanisms remain unclear.

Purpose of the Study:

  • To functionally characterize two heterozygous missense variants (p.R351T in α2δ-1 and p.A275T in α2δ-3) identified in patients with ASD.
  • To investigate the impact of these variants on α2δ protein function, membrane expression, and synaptic localization.

Main Methods:

  • Electrophysiological recordings in tsA201 cells to assess channel-dependent functions.
  • Expression studies in cultured murine hippocampal neurons to evaluate membrane expression, presynaptic targeting, and trans-synaptic signaling.

Main Results:

  • Both mutated α2δ proteins showed significantly reduced membrane expression and synaptic localization compared to wild-type.
  • The α2δ-3 A275T mutation altered glycosylation patterns.
  • Neither mutation affected the biophysical properties of associated calcium channels (CaV1.2, CaV1.3, CaV2.1).
  • Presynaptic expression of the α2δ-1 variant did not alter trans-synaptic signaling to GABA receptors.

Conclusions:

  • The studied ASD-associated α2δ protein variants do not appear to impair classical channel-dependent or trans-synaptic functions.
  • The findings suggest that ASD pathophysiology linked to these variants may involve more subtle alterations in synapse formation or neuronal network function.
  • Further research is needed to develop α2δ protein-linked disease models for ASD.