Developmental Origins of the Sturge Weber Syndrome Somatic Mutation - Abstract: Sturge Weber Syndrome (SWS) is a sporadic (non-inherited), developmental, neuro-cutaneous syndrome characterized by a capillary vascular malformation affecting the skin of the face, and abnormal capillary venous vessels in the leptomeninges of the brain and choroid. The choroidal vascular malformations lead to glaucoma, and the leptomeningeal vascular malformations lead to epilepsy, stroke-like episodes, and cognitive impairment. In 2013 we (a multi-institutional team) identified the cause of SWS by whole genome sequence analysis. The identical somatic mutation (c.548G→A, p.R183Q) in GNAQ (encoding Gαq) was identified in affected tissue that was absent in unaffected tissue from the same patients. Despite this discovery over a decade ago, to date, no fully faithful animal model of the disease has been developed. We hypothesize that the lack of a robust mouse model is due to two significant gaps in knowledge that need to be answered before any truly faithful animal model can be generated. Our central hypothesis is that SWS occurs 1) only if the causative somatic mutation occurs in a particular fetal cell type during development and 2) only when it occurs within a specific developmental time window. We recently published a mouse model of SWS, using conditional allele integrated into the endogenous locus that expresses the mutant version of GNAQ only upon Cre recombination. These mice develop vascular malformations in the embryo but are embryonic lethal. We propose to address the two gaps in knowledge listed above using our novel transgenic model to identify the developmental time window when the embryonic vascular malformations form, and then using transcriptomics, to identify the cell type in the earliest developing lesions that expresses mutation. These experiments will provide critical information about SWS pathogenesis, that will in future studies, us to then integrate this knowledge to generate a faithful mouse model - or different, organ-specific models - of the disease. In future work beyond the scope of this study, our mouse models will enable mechanistic studies on SWS pathology in the various organs affected.
