Long-range, directed migration is particularly dramatic in the cerebral cortex, where postmitotic neurons generated deep in the brain migrate to form layers with distinct form and function. In the X-linked dominant human disorder periventricular heterotopia (PH), many neurons fail to migrate and persist as nodules lining the ventricular surface. Females with PH present with epilepsy and other signs, including patent ductus arteriosus and coagulopathy, while hemizygous males die embryonically. We have identified the PH gene as filamin 1 (FLN1), which encodes an actin-cross-linking phosphoprotein that transduces ligand-receptor binding into actin reorganization, and which is required for locomotion of many cell types. FLN1 shows previously unrecognized, high-level expression in the developing cortex, is required for neuronal migration to the cortex, and is essential for embryogenesis.
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We thank the patients and their families for participating in this study, clinicians who provided patient samples in which mutations have not yet been found, and members of the Walsh lab, K. Howland, and M. H. Chen for their support and advice. We thank J. Joseph and D.-B. Shieh for help with immunohistochemistry, R. Han for help with mutation analysis, and T. Stossel and J. Hartwig for stimulating discussions and for sharing data prior to publication. This work was supported by grants from the NINDS (RO1 NS35129) and the Human Frontier Science Program (C. A. W.). C. A. W. is a scholar of the Rita Allen Foundation.