The intellectual disability and seizure disorder Börjeson-Forssman-Lehmann syndrome (BFLS) is linked to abnormal neuronal migration, according to a recent study (Neuron 78, 986–993).

BFLS is caused by mutations in the gene that encodes the nuclear protein PHF6. When Chi Zhang et al. knocked down the expression of PHF6 in developing mouse brains using RNAi in utero, they observed reduced neuron migration to the outer layers of the cortex, leading the neurons to reside in an abnormal cortical location and become hyperexcitable. The expression of mutant versions of PHF6 that are found in individuals with BFLS could not rescue the abnormal migration phenotype, suggesting that dysfunctional neuronal migration causes the disorder in humans.

Zhang et al. found that PHF6 binds the transcription factor PAF1 and that knocking down PAF1 in developing mice also induces abnormal neuronal migration. In microarray experiments, the researchers found that expression of the transmembrane protein neuroglycan C was decreased in neurons with reduced expression of PHF6 compared with wild-type neurons and that reexpression of neuroglycan C could rescue cortical neuron migration in mice with PHF6 knockdown. Whether restoring neuronal migration via this mechanism could improve cognition in BFLS remains an open question.