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Mishra-Gorur, K., Çağlayan, A.O., Schaffer, A.E., Chabu, C., Henegariu, O., Vonhoff, F., Akgümüş, G.T., Nishimura, S., Han, W., Tu, S., Baran, B., Gümüş, H., Dilber, C., Zaki, M.S., Hossni, H.A., Rivière, J.B., Kayserili, H., Spencer, E.G., Rosti, R.Ö., Schroth, J., Per, H., Çağlar, C., Çağlar, Ç., Dölen, D., Baranoski, J.F., Kumandaş, S., Minja, F.J., Erson-Omay, E.Z., Mane, S.M., Lifton, R.P., Xu, T., Keshishian, H., Dobyns, W.B., Chi, N.C., Šestan, N., Louvi, A., Bilgüvar, K., Yasuno, K., Gleeson, J.G., Günel, M. (2014). Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors.  Neuron 84(6): 1226--1239.
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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.

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PMC5024344 (PMC) (EuropePMC)
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