Identification of the Precise Developmental Window and Tissue Bed for the Somatic Mutation Causing Sturge Weber Syndrome
Abstract
Sturge Weber syndrome (SWS) is a vascular malformation disease that affects the skin (particularly, the face), the brain, and eye. It manifests within the very first few weeks of life, leading to disfiguring facial features, as well as glaucoma, seizures, stroke, and intellectual disability. It is not inherited, but occurs in a child, randomly and unexpectedly. In 2013, SWS was found to be caused by a mutation, but not a mutation that can be inherited. Instead, this mutation was found only in the affected vascular malformation tissue of affected children and adults. The mutation was found in a gene called GNAQ, providing the instructions to make a protein called Gaq. Since this gene is also mutated in certain tumors (cancers), Gaq has been extensively studied in cancer, and potential drugs are already available. The discovery of the cause of SWS as this specific somatic activating mutation brought great hope of a scientifically based treatment. In order to translate discoveries to potential drugs that can be used in clinical practice, animal models must be developed for the first test of these drugs. No naturally occurring animal develops SWS. And it has proven quite difficult to develop mouse models that will spontaneously develop a specific, somatic mutation (that is, a non-inherited mutation). It is especially difficult to generate an animal model if the somatic mutation must be induced during development in utero. This is precisely the issue for SWS. It is perhaps not surprising that no animal model has been developed for SWS, leading to a lack of studies testing potential therapies. Our proposal addresses this most difficult clinical context. We propose that two critical questions must be addressed in order to generate a mouse model of SWS. The first critical question is which cell type and tissue acquires the GNAQ somatic mutation? The second critical question is when during in utero development must the somatic mutation occur? We hypothesize that the lack of a mouse model for SWS is due to attempting to create the animal model in one step – essentially requiring to determine the correct answer to both questions at once. By contrast, my lab has now developed the mouse genetic tools (genetically engineered mice) that enable us to systematically tackle the two questions in parallel studies. Since the goal of each aim is to address a specific question but not to generate the final animal model, the experiments can run in parallel, even with one aim outpacing the other. Once both questions are addressed, we can combine the two approaches to create a SWS mouse model. While our study will focus on one particular vascular malformation, our approach can be used for other vascular malformations caused by a somatic mutation. Most importantly, what we learn about SWS pathogenesis using our model will inform us about the pathogenesis of a broad spectrum of vascular malformations. Equally important, our approach will serve as a roadmap to develop mouse models and study the pathogenesis of other congenital phenotypes that occur as a result of a somatic event occurring in utero.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110061
Entities
People
- Douglas A Marchuk
Organizations
- Duke University
- United States Army