Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia

Long-range, directed migration is particularly dramatic in the cerebral cor tex, where postmitotic neurons generated deep in the brain migrate to form layers with distinct form and function. In the X-linked dominant human diso rder periventricular heterotopia (PH), many neurons fail to migrate and per sist as nodules lining the ventricular surface. Females with PH present wit h epilepsy and other signs, including patent ductus arteriosus and coagulop athy, while hemizygous males die embryonically. We have identified the PH g ene as filamin I (FLN1), which encodes an actin-cross-linking phosphoprotei n that transduces ligand-receptor binding into actin reorganization, and wh ich is required for locomotion of many cell types. FLN1 shows previously un recognized, high-level expression in the developing cortex, is required for neuronal migration to the cortex, and is essential for embryogenesis.