{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Zecchin D"],"funding":["Great Ormond Street Hospital Childrens Charity","National Institute for Health Research (NIHR)","Wellcome Trust"],"pagination":["811-819.e4"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10957341"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["144(4)"],"pubmed_abstract":["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."],"journal":["The Journal of investigative dermatology"],"pubmed_title":["GNAQ/GNA11 Mosaicism Causes Aberrant Calcium Signaling Susceptible to Targeted Therapeutics."],"pmcid":["PMC10957341"],"funding_grant_id":["W1140","NIHR300774","210752/Z/18/Z"],"pubmed_authors":["Semple RK","Polubothu S","Thakker RV","Kinsler VA","Gluck AK","Stevenson M","Zecchin D","Inoue A","Michailidis F","Barberan-Martin S","Knopfel N","Bryant D","Lines KE","Hannan FM","Sauvadet A"],"additional_accession":[]},"is_claimable":false,"name":"GNAQ/GNA11 Mosaicism Causes Aberrant Calcium Signaling Susceptible to Targeted Therapeutics.","description":"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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Apr","modification":"2025-04-05T14:44:00.244Z","creation":"2025-04-05T14:44:00.244Z"},"accession":"S-EPMC10957341","cross_references":{"pubmed":["37802293"],"doi":["10.1016/j.jid.2023.08.028"]}}