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Qian, Xuyu; DeGennaro, Ellen M; Talukdar, Maya; Akula, Shyam K; Lai, Abbe; Shao, Diane D; Gonzalez, Dilenny; Marciano, Jack H; Smith, Richard S; Hylton, Norma K; Yang, Edward; Bazan, J Fernando; Barrett, Lee; Yeh, Rebecca C; Hill, R Sean; Beck, Samantha G; Otani, Aoi; Angad, Jolly; Mitani, Tadahiro; Posey, Jennifer E; Pehlivan, Davut; Calame, Daniel; Aydin, Hatip; Yesilbas, Osman; Parks, Kendall C; Argilli, Emanuela; England, Eleina; Im, Kiho; Taranath, Ajay; Scott, Hamish S; Barnett, Christopher P; Arts, Peer; Sherr, Elliott H; Lupski, James R; Walsh, Christopher A
Developmental cell, 10/2022, Volume: 57, Issue: 20Journal Article
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.
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