2. Academic Validation
  3. Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors

Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors

  • Neuron. 2014 Dec 17;84(6):1226-39. doi: 10.1016/j.neuron.2014.12.014.
Ketu Mishra-Gorur 1,  Ahmet Okay Çağlayan 1,  Ashleigh E Schaffer 2,  Chiswili Chabu 3,  Octavian Henegariu 1,  Fernando Vonhoff 4,  Gözde Tuğce Akgümüş 1,  Sayoko Nishimura 5,  Wenqi Han 6,  Shu Tu 7,  Burçin Baran 1,  Hakan Gümüş 8,  Cengiz Dilber 9,  Maha S Zaki 10,  Heba A A Hossni 11,  Jean-Baptiste Rivière 12,  Hülya Kayserili 13,  Emily G Spencer 2,  Rasim Ö Rosti 2,  Jana Schroth 2,  Hüseyin Per 8,  Caner Çağlar 1,  Çağri Çağlar 1,  Duygu Dölen 1,  Jacob F Baranoski 1,  Sefer Kumandaş 8,  Frank J Minja 14,  E Zeynep Erson-Omay 1,  Shrikant M Mane 15,  Richard P Lifton 3,  Tian Xu 3,  Haig Keshishian 4,  William B Dobyns 16,  Neil C Chi 7,  Nenad Šestan 17,  Angeliki Louvi 18,  Kaya Bilgüvar 15,  Katsuhito Yasuno 1,  Joseph G Gleeson 19,  Murat Günel 20
Affiliations

Affiliations

  • 1 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.
  • 2 Neurogenetics Laboratory, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
  • 3 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.
  • 4 Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511, USA.
  • 5 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.
  • 6 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.
  • 7 Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • 8 Division of Pediatric Neurology, Department of Pediatrics, Erciyes University Medical Faculty, Kayseri 38039, Turkey.
  • 9 Division of Pediatric Neurology, Department of Pediatrics, Sütcü Imam University Medical Faculty, Kahramanmaraş 46100, Turkey.
  • 10 Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Center, Cairo 12311, Egypt.
  • 11 Department of Neurology, National Institute of Neuromotor System, Cairo 12311, Egypt.
  • 12 Equipe Génétique des Anomalies du Développement, EA 4271, Université de Bourgogne, 21078 Dijon, France.
  • 13 Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul 34093, Turkey.
  • 14 Department of Radiology, Yale School of Medicine, New Haven, CT 06510, USA.
  • 15 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.
  • 16 Departments of Pediatrics and Neurology, University of Washington and Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98105, USA.
  • 17 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.
  • 18 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.
  • 19 Neurogenetics Laboratory, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: jogleeson@rockefeller.edu.
  • 20 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.
PMID: 25521378 DOI: 10.1016/j.neuron.2014.12.014
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.

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