A lissencephaly-associated BAIAP2 variant causes defects in neuronal migration during brain development

Meng Han Tsai, Wan Cian Lin, Shih Ying Chen, Meng Ying Hsieh, Fang Shin Nian, Haw Yuan Cheng, Hong Jun Zhao, Shih Shun Hung, Chi Hsin Hsu, Pei Shan Hou, Chien Yi Tung, Mei Hsuan Lee, Jin Wu Tsai

Research output: Contribution to journalJournal Article peer-review

1 Scopus citations


Lissencephaly is a neurodevelopmental disorder characterized by a loss of brain surface convolutions caused by genetic variants that disrupt neuronal migration. However, the genetic origins of the disorder remain unidentified in nearly one-fifth of people with lissencephaly. Using whole-exome sequencing, we identified a de novo BAIAP2 variant, p.Arg29Trp, in an individual with lissencephaly with a posterior more severe than anterior (P>A) gradient, implicating BAIAP2 as a potential lissencephaly gene. Spatial transcriptome analysis in the developing mouse cortex revealed that Baiap2 is expressed in the cortical plate and intermediate zone 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 the ability of BAIAP2 to localize to the cell membrane. These results suggest that the functions of BAIAP2 in the cytoskeleton, cell morphogenesis and migration are important for cortical development and for the pathogenesis of lissencephaly in humans.

Original languageEnglish
Article numberdev201912
JournalDevelopment (Cambridge)
Issue number2
StatePublished - 15 01 2024

Bibliographical note

© 2024. Published by The Company of Biologists Ltd.


  • Actin filament
  • BAIAP2
  • Cortical development
  • Developmental delay
  • Epilepsy
  • Human
  • Lissencephaly
  • Mouse
  • Neuronal migration
  • Cell Movement/genetics
  • Humans
  • Lissencephaly/genetics
  • Microtubule-Associated Proteins/genetics
  • Animals
  • Cytoskeleton/metabolism
  • Mice
  • Brain/metabolism


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