2. Academic Validation
  3. Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly

Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly

  • Am J Hum Genet. 2016 Aug 4;99(2):501-10. doi: 10.1016/j.ajhg.2016.07.004.
Hongda Li 1,  Stephanie L Bielas 2,  Maha S Zaki 3,  Samira Ismail 3,  Dorit Farfara 1,  Kyongmi Um 1,  Rasim O Rosti 1,  Eric C Scott 1,  Shu Tu 4,  Neil C Chi 4,  Stacey Gabriel 5,  Emine Z Erson-Omay 6,  A Gulhan Ercan-Sencicek 6,  Katsuhito Yasuno 6,  Ahmet Okay Çağlayan 7,  Hande Kaymakçalan 8,  Barış Ekici 8,  Kaya Bilguvar 6,  Murat Gunel 9,  Joseph G Gleeson 10
Affiliations

Affiliations

  • 1 Howard Hughes Medical Institute, Rady Children's Institute of Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA; Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, NY 10065, USA.
  • 2 Howard Hughes Medical Institute, Rady Children's Institute of Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA; Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, NY 10065, USA; Department of Human Genetics, School of Medicine, University of Michigan, Ann Arbor, 48109 MI, USA.
  • 3 Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
  • 4 Division of Cardiology, Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA.
  • 5 Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
  • 6 Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, School of Medicine, Yale University, New Haven, CT 06510, USA.
  • 7 Department of Medical Genetics, School of Medicine, Istanbul Bilim University, Istanbul 34394, Turkey.
  • 8 Department of Pediatrics, Istanbul Bilim University, Istanbul 34394, Turkey.
  • 9 Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, School of Medicine, Yale University, New Haven, CT 06510, USA. Electronic address: [email protected].
  • 10 Howard Hughes Medical Institute, Rady Children's Institute of Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA; Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, NY 10065, USA. Electronic address: [email protected].
PMID: 27453578 DOI: 10.1016/j.ajhg.2016.07.004
Abstract

Cell division terminates with cytokinesis and cellular separation. Autosomal-recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a reduction in brain and head size at birth in addition to non-progressive intellectual disability. MCPH is genetically heterogeneous, and 16 loci are known to be associated with loss-of-function mutations predominantly affecting centrosomal-associated proteins, but the multiple roles of centrosomes in cellular function has left questions about etiology. Here, we identified three families affected by homozygous missense mutations in CIT, encoding citron rho-interacting kinase (CIT), which has established roles in cytokinesis. All mutations caused substitution of conserved amino acid residues in the kinase domain and impaired kinase activity. Neural progenitors that were differentiated from induced pluripotent stem cells (iPSCs) derived from individuals with these mutations exhibited abnormal cytokinesis with delayed mitosis, multipolar spindles, and increased Apoptosis, rescued by CRISPR/Cas9 genome editing. Our results highlight the importance of cytokinesis in the pathology of primary microcephaly.

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