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Updated: Jul 14, 2025

Quantifying Spontaneous Ca2+ Fluxes and their Downstream Effects in Primary Mouse Midbrain Neurons
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GNAQ/GNA11 Mosaicism Causes Aberrant Calcium Signaling Susceptible to Targeted Therapeutics

Davide Zecchin1, Nicole Knöpfel2, Anna K Gluck3

  • 1Mosaicism and Precision Medicine Laboratory, Francis Crick Institute, London, United Kingdom; Genetics and Genomic Medicine, UCL GOS Institute of Child Health, London, United Kingdom.

The Journal of Investigative Dermatology
|October 6, 2023
PubMed

Insights

Mosaic variants in GNAQ/11 genes cause diseases like Sturge-Weber syndrome. This study found that hyperactivated calcium signaling is the key issue, suggesting targeted therapies for these vascular and pigmentary disorders.

Area of Science:

  • Genetics and Molecular Biology
  • Cellular Biology
  • Vascular Biology

Background:

  • Mosaic variants in GNAQ or GNA11 genes are associated with vascular and pigmentary diseases, including Sturge-Weber syndrome.
  • Progressive neurological deterioration in Sturge-Weber syndrome necessitates the development of targeted therapeutics.

Purpose of the Study:

  • To investigate the underlying biological mechanisms of GNAQ/11 mosaicism.
  • To identify potential therapeutic targets for GNAQ/11-related disorders.

Main Methods:

  • Utilized two cellular models to study GNAQ/11 variants.
  • Employed small interfering RNAs (siRNAs) to silence variant alleles.
  • Administered calcium-release-activated channel inhibitors.

Main Results:

  • Disease-causing GNAQ/11 variants lead to hyperactivation of intracellular calcium signaling in endothelial cells.
  • This aberrant signaling is sustained by extracellular calcium influx via calcium-release-activated channels.
  • siRNA treatment corrected both constitutive and ligand-activated calcium signaling, while channel inhibitors only rescued ligand-activated signaling.

Conclusions:

  • Hyperactivated calcium signaling is identified as the primary abnormality in GNAQ/11 mosaicism.
  • This finding supports the potential for genetic or small molecule therapies.
  • The study lays the groundwork for future clinical trials targeting these pathways.

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