A p190BRhoGAP mutation and prolonged RhoB activation in fatal systemic capillary leak syndrome

Pierce et al. describe a pediatric patient with a fatal systemic capillary leak syndrome (Clarkson’s disease). They identify a point mutation in p190BRhoGAP and show that patient-derived microvascular endothelial cells show prolonged activation RhoB that correlates with impaired barrier recovery after treatment with TNF compared with control cultures.
We describe a fatal case of pediatric systemic capillary leak (Clarkson’s disease) associated with a point mutation in p190BRhoGAP. Dermal microvascular endothelial cells (ECs) isolated from this patient form monolayers with similar levels and distribution of junctional proteins and transendothelial electrical resistance compared with normal human dermal microvascular ECs. However, patient-derived ECs demonstrate a greater increase in permeability and impaired recovery of barrier function in response to tumor necrosis factor (TNF) compared with normal donor EC cultures. TNF transiently activates RhoB in ECs coincident with developing leak, and inactivation of RhoB correlates with barrier recovery. The mutation in p190BRhoGAP impairs RhoB inactivation, and the mutant phenotype of patient-derived ECs is replicated by siRNA knockdown of p190BRhoGAP in normal ECs. These data suggest a previously unknown function for p190BRhoGAP in control of capillary EC barrier function that may also be important in acquired systemic capillary leak associated with critical illness in humans.