GNAQ/GNA11 mosaicism causes aberrant calcium signalling susceptible to targeted therapeutics

  • J Invest Dermatol. 2023 Sep 29:S0022-202X(23)02603-9. doi: 10.1016/j.jid.2023.08.028.
Davide Zecchin  1 ,  Nicole Knöpfel  2 ,  Anna K Gluck  3 ,  Mark Stevenson  3 ,  Aimie Sauvadet  1 ,  Satyamaanasa Polubothu  2 ,  Sara Barberan-Martin  1 ,  Fanourios Michailidis  1 ,  Dale Bryant  1 ,  Asuka Inoue  4 ,  Kate E Lines  3 ,  Fadil M Hannan  5 ,  Robert K Semple  6 ,  Rajesh V Thakker  7 ,  Veronica A Kinsler  8
Affiliations
  • 1. Mosaicism and Precision Medicine Laboratory, Francis Crick Institute; London NW1 1AT, UK; Genetics and Genomic Medicine, UCL GOS Institute of Child Health; London WC1N 1EH, UK.
  • 2. Mosaicism and Precision Medicine Laboratory, Francis Crick Institute; London NW1 1AT, UK; Genetics and Genomic Medicine, UCL GOS Institute of Child Health; London WC1N 1EH, UK; Department of Paediatric Dermatology, Great Ormond St Hospital for Children; London WC1N 3JH, UK.
  • 3. Academic Endocrine Unit, Radcliffe Department of Medicine,University of Oxford; Oxford OX3 7LJ, UK.
  • 4. Graduate School of Pharmaceutical Sciences, Tohoku University; Sendai 980-8578, Japan.
  • 5. Nuffield Department of Women's & Reproductive Health, University of Oxford; Oxford, United Kingdom.
  • 6. Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh; Edinburgh, UK.
  • 7. Academic Endocrine Unit, Radcliffe Department of Medicine,University of Oxford; Oxford OX3 7LJ, UK; National Institute for Health Research Oxford Biomedical Research Centre; Oxford, UK.
  • 8. Mosaicism and Precision Medicine Laboratory, Francis Crick Institute; London NW1 1AT, UK; Genetics and Genomic Medicine, UCL GOS Institute of Child Health; London WC1N 1EH, UK; Department of Paediatric Dermatology, Great Ormond St Hospital for Children; London WC1N 3JH, UK. Electronic address: [email protected].
PMID: 37802293 DOI: 10.1016/j.jid.2023.08.028
Abstract

Mosaic variants in genes GNAQ or GNA11 lead to a spectrum of vascular and pigmentary diseases including Sturge-Weber syndrome, in which progressive post-natal neurological deterioration led us to seek biologically-targeted therapeutics. Using two cellular models we find here that disease-causing GNAQ/11 variants hyperactivate constitutive and GPCR ligand-induced intracellular calcium signalling in endothelial cells. We go on to show that the aberrant ligand-activated intracellular calcium signal is fuelled by extracellular calcium influx through CRAC channels. Treatment with targeted siRNAs designed to silence the variant allele preferentially corrects both the constitutive and ligand-activated calcium signalling, whilst treatment with a CRAC Channel Inhibitor rescues the ligand-activated signal. This work identifies hyperactivated calcium signalling as the primary abnormality in GNAQ/11 mosaicism, and paves the way for clinical trials with genetic or small molecule therapies.

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