GNAQ/GNA11 Mosaicism Causes Aberrant Calcium Signaling Susceptible to Targeted Therapeutics

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.