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.
Bibliographical noteFunding Information:
We thank the patients and families who contributed to this study. This work was supported by the Yale Program on Neurogenetics and National Institutes of Health (NIH) Grants U54HG006504 (Yale Center for Mendelian Disorders, to R.P.L., M.G., M. Gerstein, and S.M.M.), U01MH081896 (to N.Š.), and R01MH103616 (to M.G. and K.B.). This work was also supported by R01NS041537 and P01HD070494 (to J.G.G. and N.C.C.). R.P.L. and J.G.G. are Investigators of the Howard Hughes Medical Institute. We are grateful to the Gregory M. Kiez and Mehmet Kutman Foundation for continuing support.