Seizures in Sturge-Weber syndrome are associated with disrupted calcium metabolism

Mosaic mutations in genes GNAQ or GNA11 lead to a spectrum of diseases including Sturge-Weber syndrome. Progressive post-natal neurological deterioration led us to seek biologically-targeted therapeutics, and neurovascular calcification to hypothesise that calcium metabolism was pathogenetically central. Calcium signaling was assessed in two cell models expressing GNAQ(c.548G>A,p.(R183Q)) and GNA11(c.547C>T,p.(R183C)). We designed mutant-allele-specific siRNAs and employed these and CRAC channel inhibitor CM4260 to test the biological pathways. We show here that GNAQ/11 mutations cause constitutive and hyperactive GPCR ligand-induced intracellular calcium signaling, which in turn drives extracellular calcium influx and abnormal angiogenesis. Treatment with CM4260 or mutant-specific siRNAs rescues the cellular abnormalities. We go on to demonstrate previously unsuspected disruption of systemic calcium metabolism in 42 patients, despite normally functioning parathyroid, skeletal and renal systems. Critically, levels of serum ionised calcium in the patients cohort as a whole were significantly associated with the presence of seizures (p=0.013) and occurrence of status epilepticus (p=0.017). These data demonstrate that GNAQ/11 mosaicism are fundamentally abnormalities of calcium signaling and handling, that it is related to serious neurological adverse outcomes, and that at cellular level it is druggable. These findings will lead directly to clinical trials.