title: Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, USA; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Ketu
authors.initials: K
authors.lastname: Mishra-Gorur
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, USA; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Ahmet Okay
authors.initials: AO
authors.lastname: Çağlayan
authors.affiliation: Neurogenetics Laboratory, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ashleigh E
authors.initials: AE
authors.lastname: Schaffer
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Chiswili
authors.initials: C
authors.lastname: Chabu
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, USA; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Octavian
authors.initials: O
authors.lastname: Henegariu
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Vonhoff
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, USA; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Gözde Tuğce
authors.initials: GT
authors.lastname: Akgümüş
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, USA; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Sayoko
authors.initials: S
authors.lastname: Nishimura
authors.affiliation: Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA; Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Han
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Tu
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, USA; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Burçin
authors.initials: B
authors.lastname: Baran
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Erciyes University Medical Faculty, Kayseri 38039, Turkey.
authors.forename: Hakan
authors.initials: H
authors.lastname: Gümüş
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Sütcü Imam University Medical Faculty, Kahramanmaraş 46100, Turkey.
authors.forename: Cengiz
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authors.lastname: Dilber
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Center, Cairo 12311, Egypt.
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.affiliation: Department of Neurology, National Institute of Neuromotor System, Cairo 12311, Egypt.
authors.forename: Heba A A
authors.initials: HA
authors.lastname: Hossni
authors.affiliation: Equipe Génétique des Anomalies du Développement, EA 4271, Université de Bourgogne, 21078 Dijon, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Rivière
authors.affiliation: Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul 34093, Turkey.
authors.forename: Hülya
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authors.lastname: Kayserili
authors.affiliation: Neurogenetics Laboratory, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Emily G
authors.initials: EG
authors.lastname: Spencer
authors.affiliation: Neurogenetics Laboratory, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Rasim Ö
authors.initials: RÖ
authors.lastname: Rosti
authors.affiliation: Neurogenetics Laboratory, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jana
authors.initials: J
authors.lastname: Schroth
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Erciyes University Medical Faculty, Kayseri 38039, Turkey.
authors.forename: Hüseyin
authors.initials: H
authors.lastname: Per
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, USA; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Caner
authors.initials: C
authors.lastname: Çağlar
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, USA; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Çağri
authors.initials: Ç
authors.lastname: Çağlar
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, USA; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Duygu
authors.initials: D
authors.lastname: Dölen
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, USA; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Jacob F
authors.initials: JF
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authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Erciyes University Medical Faculty, Kayseri 38039, Turkey.
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authors.lastname: Kumandaş
authors.affiliation: Department of Radiology, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Minja
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, USA; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: E Zeynep
authors.initials: EZ
authors.lastname: Erson-Omay
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Shrikant M
authors.initials: SM
authors.lastname: Mane
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Richard P
authors.initials: RP
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authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511, USA.
authors.forename: Haig
authors.initials: H
authors.lastname: Keshishian
authors.affiliation: Departments of Pediatrics and Neurology, University of Washington and Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98105, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Neil C
authors.initials: NC
authors.lastname: Chi
authors.affiliation: Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA; Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Nenad
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authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Louvi
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT 06510, USA.
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authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, USA; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Katsuhito
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authors.lastname: Yasuno
authors.affiliation: Neurogenetics Laboratory, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: jogleeson@rockefeller.edu.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, USA; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address: murat.gunel@yale.edu.
authors.forename: Murat
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mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000002:abnormalities* / Q000254:growth & development / Q000473:pathology*; D002452:Cell Count; D002455:Cell Division / Q000235:genetics; D003712:Dendrites / Q000235:genetics; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics; D006801:Humans; D000074201:Katanin; D051379:Mice; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009154:Mutation; D058953:Neural Stem Cells / Q000473:pathology*; D055495:Neurogenesis / Q000235:genetics*; D009899:Optic Lobe, Nonmammalian / Q000002:abnormalities*; D008941:Spindle Apparatus / Q000235:genetics; D015027:Zebrafish
chemical_list: D029721:Drosophila Proteins; D008869:Microtubule-Associated Proteins; D000251:Adenosine Triphosphatases; D000074201:Katanin