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

Actin filament; BAIAP2; Cortical development; Developmental delay; Epilepsy; Human; Lissencephaly; Mouse; Neuronal migration; Animals; Brain; Cell Movement; Cytoskeleton; Humans; Mice; Microtubule-Associated Proteins; baiap2 protein; glial fibrillary acidic protein; guanosine triphosphatase; protein; short hairpin RNA; transcriptome; unclassified drug; microtubule associated protein; agyria; animal experiment; Article; brain cortex; brain development; brain slice; case report; cell differentiation; cell function; cell membrane; cell migration; cellular distribution; child; clinical article; controlled study; cytoskeleton; developmental delay; developmental stage; electroencephalogram; electroporation; embryo; family history; gene expression profiling; genetic screening; genetic variability; human; immunofluorescence; ketogenic diet; morphogenesis; mouse; neuroimaging; nonhuman; oligodendroglia; pathogenesis; phenotype; preschool child; protein expression; refractory epilepsy; Sanger sequencing; single nucleotide polymorphism; speech development; Taiwan; tonic clonic seizure; Western blotting; whole exome sequencing; animal; brain; cell motion; genetics; metabolism

Abstract :

[en] 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. © 2024. Published by The Company of Biologists Ltd.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Tsai, M.-H.; Department of Neurology, Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 833, Taiwan

Lin, W.-C.; School of Medicine, Chang Gung University, Taoyuan, 333, Taiwan

Chen, S.-Y.; Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan

Hsieh, M.-Y.; Faculty of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan

Nian, Fang-Shin ; Université de Liège - ULiège > GIGA > GIGA Neurosciences - Molecular Regulation of Neurogenesis ; Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan

Cheng, Haw-Yuan ; Université de Liège - ULiège > GIGA > GIGA Neurosciences - Molecular Regulation of Neurogenesis ; Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan

Zhao, H.-J.; Institute of Anatomy and Cell Biology, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan

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

Hsu, C.-H.; Advanced Therapeutics Research Center, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan

Hou, P.-S.; Brain Research Center, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan

More authors (3 more)

Language :

English

Title :

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

Publication date :

2024

Journal title :

Development

ISSN :

0950-1991

eISSN :

1477-9129

Publisher :

Company of Biologists Ltd

Volume :

151

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85182957880&doi=10.1242%2fdev.201912&partnerID=40&md5=97acc1fe4fffdebb4ab03917010c9d2f

Available on ORBi :

since 14 April 2025

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