TY - JOUR
T1 - GNAQ/GNA11 Mosaicism Causes Aberrant Calcium Signaling Susceptible to Targeted Therapeutics
AU - Zecchin, Davide
AU - Knöpfel, Nicole
AU - Gluck, Anna K.
AU - Stevenson, Mark
AU - Sauvadet, Aimie
AU - Polubothu, Satyamaanasa
AU - Barberan-Martin, Sara
AU - Michailidis, Fanourios
AU - Bryant, Dale
AU - Inoue, Asuka
AU - Lines, Kate E.
AU - Hannan, Fadil M.
AU - Semple, Robert K.
AU - Thakker, Rajesh V.
AU - Kinsler, Veronica A.
N1 - We gratefully acknowledge the research coordination by Jane White. VK and NK are funded by the UK NIHR (grant NIHR300774). This work was supported by the GOSHCC Livingstone 15 Skin Research Centre, a Lisa's Fellowship from the Sturge-Weber Foundation Research Network, by a pump-priming grant from Associazione Sindrome di Sturge Weber Italia ONLUS, and by the UK National Institute for Health Research (NIHR) through the Biomedical Research Centre at Great Ormond St Hospital for Children NHS Foundation Trust and the UCL GOS Institute of Child Health. R.V.T. was funded by a grant (106995/Z/15/Z) from the Wellcome Trust, a grant from the Oxford Biomedical Research Centre Program of the National Institute for Health Research (NIHR), a grant (NF-SI-0514–10091) from the NIHR. R.K.S. was funded by a grant (210752/Z/18/Z) from the Wellcome Trust. A.I. was funded by Japan
Society for the Promotion of Science (JSPS) KAKENHI grants 21H04791 and 21H05113; Moonshot Research and Development Program JPMJMS2023 from Japan Science and Technology Agency (JST); the the LEAP JP20gm0010004 and the BINDS JP20am0101095 from the Japan Agency for Medical Research and Development (AMED); Daiichi Sankyo Foundation of Life Science; Takeda Science Foundation; The Uehara Memorial Foundation; The Tokyo Biochemical Research Foundation
PY - 2023/10/4
Y1 - 2023/10/4
N2 - 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.
AB - 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.
U2 - 10.1016/j.jid.2023.08.028
DO - 10.1016/j.jid.2023.08.028
M3 - Article
SN - 0022-202X
VL - 144
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 4
M1 - 811-819.e4
ER -