The Francis Crick Institute
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GNAQ/GNA11 mosaicism causes aberrant calcium signalling susceptible to targeted therapeutics

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journal contribution
posted on 2024-03-21, 09:44 authored by Davide Zecchin, Nicole Knöpfel, Anna K Gluck, Mark Stevenson, Aimie Sauvadet, Satyamaanasa Polubothu, Sara Barberan-Martin, Fanourios Michailidis, Dale Bryant, Asuka Inoue, Kate E Lines, Fadil M Hannan, Robert K Semple, Rajesh V Thakker, Veronica A Kinsler
Mosaic variants in genes GNAQ or GNA11 lead to a spectrum of vascular and pigmentary diseases including Sturge-Weber syndrome, in which progressive postnatal neurological deterioration led us to seek biologically targeted therapeutics. Using two cellular models, we find that disease-causing GNAQ/11 variants hyperactivate constitutive and G-protein coupled receptor ligand-induced intracellular calcium signaling in endothelial cells. We go on to show that the aberrant ligand-activated intracellular calcium signal is fueled by extracellular calcium influx through calcium-release-activated channels. Treatment with targeted small interfering RNAs designed to silence the variant allele preferentially corrects both the constitutive and ligand-activated calcium signaling, whereas treatment with a calcium-release-activated channel inhibitor rescues the ligand-activated signal. This work identifies hyperactivated calcium signaling as the primary biological abnormality in GNAQ/11 mosaicism and paves the way for clinical trials with genetic or small molecule therapies.