Identification of Genes Associated with Cortical Malformation Using a Transposon-Mediated Somatic Mutagenesis Screen in Mice
Abstract number :
1.017
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2019
Submission ID :
2421013
Source :
www.aesnet.org
Presentation date :
12/7/2019 6:00:00 PM
Published date :
Nov 25, 2019, 12:14 PM
Authors :
Hsin-Hung Chen, Taipei Veterans General Hospital; I-Ling Lu, National Yang-Ming University; Jin-Wu Tsai, National Yang-Ming University; Chien Chen, Taipei Veterans General Hospital
Rationale: Mutations in genes involved in the production, migration, or differentiation of cortical neurons often lead to malformations of cortical development (MCDs). However, many genetic mutations involved in MCD pathogenesis remain unidentified. Methods: Here we developed a genetic screening paradigm based on transposon-mediated somatic mutagenesis by in utero electroporation and the inability of mutant neuronal precursors to migrate to the cortex and identified 33 candidate MCD genes. Results: Consistent with the screen, several genes have already been implicated in neural development and disorders. Functional disruption of the candidate genes by RNAi or CRISPR/Cas9 causes altered neuronal distributions that resemble human cortical dysplasia. To verify potential clinical relevance of these candidate genes, we analyzed somatic mutations in brain tissue from patients with focal cortical dysplasia and found that mutations are enriched in these candidate genes. Conclusions: These results demonstrate that this approach is able to identify potential mouse genes involved in cortical development and MCD pathogenesis. Funding: No funding
Basic Mechanisms