Sturge-Weber syndrome (SWS) is a rare, congenital but sporadic disease characterized by a facial port-wine birthmark, choroidal and leptomeningeal vascular malformations, epilepsy, stroke-like episodes, headache, and cognitive impairment. The disease is characterized by ongoing vascular overgrowth;histopathological studies of SWS lesion tissue show abnormal expression of vascular phenotypes and angiogenic factors. Angiogenic factors correlate with clinical severity suggesting that vascular remodeling is important in SWS. We hypothesize that vascular remodeling is ongoing in SWS, is central to the clinical progression, and is related to the recently discovered pathogenic somatic mutation in GNAQ. The causative somatic mutation for SWS is an activating mutation in the GNAQ gene, a guanine nucleotide binding protein essential in transmitting signals from G-protein coupled receptors (GPCRs), many of which are essential to vascular development and function. With this new knowledge, we will investigate our central hypotheses and prepare for treatment trials with clinical, biochemical, and molecular analyses. In Project 2, our database will continue to capture SWS patients across the nation as they are seen at Sturge-Weber Foundation (SWF) Centers of Excellence. This database is the first national SWS database with longitudinal clinical data and this effort has integrated seven clinical research centers. We now propose to take the next steps in multi-centered clinical research and engage in longitudinal multi-centered clinical research that will quantify vascular remodeling in subjects with SWS, develop new biomarkers, and propose a safety drug study as a pilot project. We will also build upon the remarkable success of our first round of funding, the discovery of the somatic mosaic mutation in GNAQ that causes SWS, and determine the impact of this genetic defect upon downstream proteins and pathways in SWS skin and brain tissue. The illumination of the molecular genetic pathways of SWS will suggest new avenues for future development of therapy.

Public Health Relevance

Sturge-Weber Syndrome (SWS) is a rare, congenital but sporadic disease characterized by ongoing vascular overgrowth. We hypothesize that vascular remodeling is ongoing in SWS and is related to to the recently discovered pathogenic somatic mutation in GNAQ. With this new knowledge, we will investigate our central hypotheses and prepare for treatment trials.

National Institute of Health (NIH)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZTR1)
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Moy, Claudia S
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University of California San Francisco
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