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

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Lissencephaly is a neurodevelopmental disorder resulting from disrupted neuronal migration.
• Genetic causes remain unknown in a significant portion of lissencephaly cases.

Purpose of the Study:

• To identify novel genetic causes of lissencephaly.
• To investigate the role of BAIAP2 in cortical development and lissencephaly pathogenesis.

Main Methods:

• Whole-exome sequencing to identify genetic variants.
• Spatial transcriptome analysis in mouse cortex.
• In utero electroporation to study gene function in vivo.

Main Results:

• A de novo BAIAP2 variant (p.Arg29Trp) was identified in an individual with lissencephaly.
• Baiap2 exhibits an anterior-to-posterior expression gradient in the developing mouse cortex.
• Baiap2 knockdown impaired neuronal migration, morphogenesis, and differentiation; the identified variant caused a loss-of-function effect.

Conclusions:

• BAIAP2 is implicated as a novel gene in lissencephaly.
• BAIAP2 is essential for proper neuronal migration and cortical development.
• The p.Arg29Trp variant disrupts BAIAP2 function, contributing to lissencephaly pathogenesis.