Chorea-acanthocytosis is an eventually lethal genetic disease leading to progressive disorders of movement, cognitive function and behavior, chronic hyperkalemia and variable red blood cell acanthocytosis. The disease is caused by loss of function mutations of VPS13A encoding chorein, a protein of unknown function, which is expressed in a wide variety of cells. Little is known about the mechanisms linking chorein deficiency to the spectacular shape change of erythrocytes and to the simultaneous deterioration of neuromuscular function. The present study reveals that cell membrane phospholipid assymmetry is preserved and cell volume normal but that cortical actin is depolymerized in erythrocytes from patients with chorea-acanthocytosis. Silencing of chorein in K562 cells led to similar depolymerization of cortical actin with the respective significant increase in soluble actin. As cortical actin is a powerful regulator of exocytosis, membrane protein trafficking and membrane blebbing, the depolymerization of cortical actin is expected to influence the function of a wide variety of cells.