RIDES

Small GTPases of the Rho family, their regulators and their effectors assemble molecular platforms at the surface of membranes that control multiple signaling pathways. These signaling platforms are involved in various physiological functions and processes in the cell, such as the regulation of the cytoskeleton, adhesion, migration or the cell cycle. Mirroring these major functions, their deregulations can be at the origin of human pathologies such as cancer and developmental abnormalities. However, how molecular defects in Rho pathways result in clinical symptoms is extremely complex and has remained poorly understood. In this project, we identified patients with missense mutations affecting the small GTPases CDC42 and RHOA, as well as in the upstream regulators DOCK1, a guanine nucleotide exchange factor (GEF) that stimulates their activation by GDP/GTP exchange, and Galpha13, a subunit of a heterotrimeric G protein that recruits a Rho GEF, all of which result in a spectrum of disabling skin diseases, often with inflammatory symptoms. These rare skin diseases provide a unique opportunity to unravel the inner workings of Rho GTPases molecular circuits from the molecule to the patient. With this aim, this project gathers four laboratories with an unusual range of complementary expertise, including biochemistry and structural biology, cell biology, genetics and medicine. This consortium will investigate the mutational landscape of the Rho pathways in a large and unique cohort of patients with skin disorders, identify the biochemical and cellular defects associated with the mutations, and determine the impact of the mutations on Rho GTPase functions and in signaling pathways regulated by Rho GTPases in cells and in an in vivo genetics model. The project should thus impact fundamental and translational research in several ways. First, through its multiscale approach, it should offer an unprecedented understanding of Rho GTPase functions and their crosstalk with major signaling pathways. Thus, it is anticipated to have an important impact on the broad community of researchers working in the field of small GTPase biology. Second, it should deliver integrated experimental protocols for deciphering molecular defects in patients with conditions caused by small GTPase mutations. Such diseases are increasingly being recognised, as exemplified by results from the MUSTARD cohort at the reference centre for mosaic skin diseases in Dijon, and represent unique medical models of rare diseases. Finally, it should allow to design novel targeted drug therapy for these patients, and possibly for more common autoinflammatory diseases, directly aimed at their functional and molecular defects. Our preliminary results suggest that such approach may include repurposing of market-approved drugs.