Lissencephaly-associated BAIAP2 variant causes defects in neuronal migration during brain development.

Lissencephaly is a neurodevelopmental disorder characterized by a loss of brain surface convolutions caused by genetic variants that disrupt neuronal migration. However, genetic origins in nearly one-fifth of lissencephaly patients remain unidentified. Using whole exome sequencing (WES), we identified a de novo BAIAP2 variant p.Arg29Trp in a lissencephaly patient with a posterior more severe than anterior (P>A) gradient, implicating BAIAP2 as a potential lissencephaly gene. Spatial transcriptome analysis in the developing cortex revealed that Baiap2 was expressed in the cortical plate (CP) and intermediate zone (IZ) in an anterior low to posterior high gradient. We next used in utero electroporation to explore the effects of the Baiap2 variant in the developing mouse cortex. We found that Baiap2 knockdown caused abnormalities in neuronal migration, morphogenesis, and differentiation. Expression of the p.Arg29Trp variant failed to rescue the migration defect, suggesting a loss-of-function effect. Mechanistically, the variant interfered with BAIAP2's ability to localize to the cell membrane. These results suggest that BAIAP2's functions in the cytoskeleton, cell morphogenesis, and migration are important for cortical development and the pathogenesis of lissencephaly in humans.

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