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Am J Hum Genet. 2016 Aug 4;99(2):501-10. doi: 10.1016/j.ajhg.2016.07.004. Epub 2016 Jul 21.

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

Author information

  • 1Howard 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.
  • 2Howard 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.
  • 3Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
  • 4Division of Cardiology, Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA.
  • 5Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
  • 6Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, School of Medicine, Yale University, New Haven, CT 06510, USA.
  • 7Department of Medical Genetics, School of Medicine, Istanbul Bilim University, Istanbul 34394, Turkey.
  • 8Department of Pediatrics, Istanbul Bilim University, Istanbul 34394, Turkey.
  • 9Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, School of Medicine, Yale University, New Haven, CT 06510, USA. Electronic address: murat.gunel@yale.edu.
  • 10Howard 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: jogleeson@ucsd.edu.

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.

PMID:
27453578
PMCID:
PMC4974110
DOI:
10.1016/j.ajhg.2016.07.004
[PubMed - in process]
Free PMC Article
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