Actinopathies related to DOCK11 deficiencies – ActiDOCK

Actin is a cellular compound that forms fibers that support the skeleton of cells (cytoskeleton). Actin remodeling is a biological process that allows the cell to move and deform to migrate through body tissues. This process is finely regulated by intracellular signals and in particular by the DOCK (Dedicator of Cytokinesis) proteins. Mutations in the gene encoding DOCK8 are found in patients who present with an immune deficiency with a high susceptibility to viral infections. They are the consequence of a lack of migration of certain white blood cells in the infected tissues. In 7 patients with autoimmune diseases, we have recently identified, mutations of DOCK11, which encodes the DOCK11 protein, whose cellular function is still imperfectly understood. Our preliminary results indicate that DOCK11 deficiency is associated with aberrant cellular architecture deformation and mobility of patient cells. This discovery identifies a new pathology associated with an anomaly of the actin cytoskeleton (Actinopathy) in the context of autoimmune diseases, suggesting that DOCK11 could be essential to the cells ensuring immune tolerance. In order to better understand the role of DOCK11, we will carry out molecular and functional studies on cells from patients carrying DOCK11 mutations, and we will compare them to cells from patients carrying DOCK8 and WAS mutations, found in immune-related actinopathies. This project will allow us to carry out a fine molecular mapping of these pathologies, to better understand the physiological function of DOCK11 and potentially to identify specific therapeutic targets for this severe autoimmune disease in children.