TY - JOUR
T1 - Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors
AU - Mishra-Gorur, Ketu
AU - Çağlayan, Ahmet Okay
AU - Schaffer, Ashleigh E.
AU - Chabu, Chiswili
AU - Henegariu, Octavian
AU - Vonhoff, Fernando
AU - Akgümüş, Gözde Tuğce
AU - Nishimura, Sayoko
AU - Han, Wenqi
AU - Tu, Shu
AU - Baran, Burçin
AU - Gümüş, Hakan
AU - Dilber, Cengiz
AU - Zaki, Maha S.
AU - Hossni, Heba A.A.
AU - Rivière, Jean Baptiste
AU - Kayserili, Hülya
AU - Spencer, Emily G.
AU - Rosti, Rasim
AU - Schroth, Jana
AU - Per, Hüseyin
AU - Çağlar, Caner
AU - Çağlar, Çağri
AU - Dölen, Duygu
AU - Baranoski, Jacob F.
AU - Kumandaş, Sefer
AU - Minja, Frank J.
AU - Erson-Omay, E. Zeynep
AU - Mane, Shrikant M.
AU - Lifton, Richard P.
AU - Xu, Tian
AU - Keshishian, Haig
AU - Dobyns, William B.
AU - Chi, Neil C.
AU - Šestan, Nenad
AU - Louvi, Angeliki
AU - Bilgüvar, Kaya
AU - Yasuno, Katsuhito
AU - Gleeson, Joseph G.
AU - Günel, Murat
N1 - Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2014/12/17
Y1 - 2014/12/17
N2 - 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.
AB - 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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U2 - 10.1016/j.neuron.2014.12.014
DO - 10.1016/j.neuron.2014.12.014
M3 - Article
C2 - 25521378
AN - SCOPUS:84926392444
SN - 0896-6273
VL - 84
SP - 1226
EP - 1239
JO - Neuron
JF - Neuron
IS - 6
ER -