Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors

Exome sequencing analysis of over 2,000 children with complex malformations of cortical development identified five independent (four homozygous and one compound heterozygous) deleterious mutations in KATNB1, encoding the regulatory subunit of the microtubule-severing enzyme Katanin. Mitotic spindle formation is defective in patient-derived fibroblasts, a consequence of disrupted interactions of mutant KATNB1 with KATNA1, the catalytic subunit of Katanin, and other microtubule-associated proteins. Loss of KATNB1 orthologs in zebrafish (katnb1) and flies (kat80) results in microcephaly, recapitulating the human phenotype. In the developing Drosophila optic lobe, kat80 loss specifically affects the asymmetrically dividing neuroblasts, which display supernumerary centrosomes and spindle abnormalities during mitosis, leading to cell cycle progression delays and reduced cell numbers. Furthermore, kat80 depletion results in dendritic arborization defects in sensory and motor neurons, affecting neural architecture. Taken together, we provide insight into the mechanisms by which KATNB1 mutations cause human cerebral cortical malformations, demonstrating its fundamental role during brain development. •Mutations in KATNB1 (katanin B1) cause cerebral cortical malformations•Mutations affect interaction of KATNB1 with NDEL1 and KATNA1•kat80 depletion results in increased number of centrosomes•kat80 loss in Drosophila preferentially affects asymmetrically dividing neuroblasts Mishra-Gorur et al. associate homozygous mutations in KATNB1, encoding a subunit of the microtubule-severing enzyme katanin, with complex developmental brain malformations in humans and demonstrate that KATNB1 dysfunction impacts mitotic spindle formation, asymmetric cell division, and dendritic arborization in Drosophila.