2. Academic Validation
  3. GNAQ/GNA11 mosaicism causes aberrant calcium signalling susceptible to targeted therapeutics

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

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: v.kinsler@ucl.ac.uk.
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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