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

Author:

Tsai Meng-Han12,Lin Wan-Cian34,Chen Shih-Ying1,Hsieh Meng-Ying5,Nian Fang-Shin36,Cheng Haw-Yuan3,Zhao Hong-Jun3,Hung Shih-Shun7,Hsu Chi-Hsin8,Hou Pei-Shan7,Tung Chien-Yi8,Lee Mei-Hsuan69,Tsai Jin-Wu391011ORCID

Affiliation:

1. Kaohsiung Chang Gung Memorial Hospital 1 Department of Neurology & Department of Medical Research , , Kaohsiung 833 , Taiwan

2. School of Medicine, Chang Gung University 2 , Taoyuan 333 , Taiwan

3. Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University 3 , Taipei 112 , Taiwan

4. College of Medicine, National Yang Ming Chiao Tung University 4 Faculty of Medicine , , Taipei 112 , Taiwan

5. Department of Pediatrics, Chang Gung Memorial Hospital 5 Division of Pediatric Neurology , , Taipei 105 , Taiwan

6. Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University 6 , Taipei 112 , Taiwan

7. Institute of Anatomy and Cell Biology, National Yang Ming Chiao Tung University 7 , Taipei 112 , Taiwan

8. Genomics Center for Clinical and Biotechnological Applications, Cancer Progression Research Center, National Yang Ming Chiao Tung University 8 , Taipei 112 , Taiwan

9. 9 Advanced Therapeutics Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan

10. National Yang Ming Chiao Tung University 10 Brain Research Center , , Taipei 112 , Taiwan

11. College of Biological Science and Technology, National Yang Ming Chiao Tung University 11 Department of Biological Science and Technology , , Hsinchu 300 , Taiwan

Abstract

ABSTRACT 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.

Funder

National Science and Technology Council

National Health Research Institutes

Brain Research Center, National Yang-Ming University

Ministry of Education

Chang Gung Medical Foundation

Publisher

The Company of Biologists

Subject

Developmental Biology,Molecular Biology

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