1. Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis.
- Author
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Qian, Xuyu, DeGennaro, Ellen, Talukdar, Maya, Akula, Shyam, Lai, Abbe, Shao, Diane, Gonzalez, Dilenny, Marciano, Jack, Smith, Richard, Hylton, Norma, Yang, Edward, Bazan, J, Barrett, Lee, Yeh, Rebecca, Hill, R, Beck, Samantha, Otani, Aoi, Angad, Jolly, Mitani, Tadahiro, Posey, Jennifer, Pehlivan, Davut, Calame, Daniel, Aydin, Hatip, Yesilbas, Osman, Parks, Kendall, England, Eleina, Im, Kiho, Taranath, Ajay, Scott, Hamish, Barnett, Christopher, Arts, Peer, Sherr, Elliott, Lupski, James, Walsh, Christopher, and Argilli, Emanuela
- Subjects
apoptosis ,cerebral cortex ,congenital brain malformation ,corpus callosum ,development ,genetics ,kinesin ,migration ,organoid ,Humans ,Animals ,Mice ,Kinesins ,Neurons ,Focal Adhesion Protein-Tyrosine Kinases ,Apoptosis ,Brain - Abstract
Kinesins are canonical molecular motors but can also function as modulators of intracellular signaling. KIF26A, an unconventional kinesin that lacks motor activity, inhibits growth-factor-receptor-bound protein 2 (GRB2)- and focal adhesion kinase (FAK)-dependent signal transduction, but its functions in the brain have not been characterized. We report a patient cohort with biallelic loss-of-function variants in KIF26A, exhibiting a spectrum of congenital brain malformations. In the developing brain, KIF26A is preferentially expressed during early- and mid-gestation in excitatory neurons. Combining mice and human iPSC-derived organoid models, we discovered that loss of KIF26A causes excitatory neuron-specific defects in radial migration, localization, dendritic and axonal growth, and apoptosis, offering a convincing explanation of the disease etiology in patients. Single-cell RNA sequencing in KIF26A knockout organoids revealed transcriptional changes in MAPK, MYC, and E2F pathways. Our findings illustrate the pathogenesis of KIF26A loss-of-function variants and identify the surprising versatility of this non-motor kinesin.
- Published
- 2022