Mutations of KIF14 cause primary microcephaly by impairing cytokinesis

  • Ann Neurol. 2017 Oct;82(4):562-577. doi: 10.1002/ana.25044.
Abubakar Moawia  1  2  3 ,  Ranad Shaheen  4 ,  Sajida Rasool  1  5 ,  Syeda Seema Waseem  1  2  3 ,  Nour Ewida  4 ,  Birgit Budde  1 ,  Amit Kawalia  1 ,  Susanne Motameny  1 ,  Kamal Khan  3 ,  Ambrin Fatima  3 ,  Muhammad Jameel  3 ,  Farid Ullah  3 ,  Talia Akram  3 ,  Zafar Ali  3 ,  Uzma Abdullah  3 ,  Saba Irshad  5 ,  Wolfgang Höhne  1 ,  Angelika Anna Noegel  1  2  6  7 ,  Mohammed Al-Owain  8 ,  Konstanze Hörtnagel  9 ,  Petra Stöbe  9 ,  Shahid Mahmood Baig  3 ,  Peter Nürnberg  1  6  7 ,  Fowzan Sami Alkuraya  4  10 ,  Andreas Hahn  11 ,  Muhammad Sajid Hussain  1  2  6
Affiliations
  • 1. Cologne Center for Genomics, University of Cologne, Cologne, Germany.
  • 2. Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.
  • 3. Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering, Pakistan Institute of Engineering and Applied Sciences, Faisalabad, Pakistan.
  • 4. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 5. Institute of Biochemistry and Biotechnology, Quaid-e-Azam Campus, University of the Punjab, Lahore, Pakistan.
  • 6. Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
  • 7. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
  • 8. Department of Medical Genetics, King Faisal Specialist Hospital, Riyadh, Saudi Arabia.
  • 9. Center for Genomics and Transcriptomics, Tübingen, Germany.
  • 10. Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
  • 11. Department of Child Neurology, University of Giessen, Giessen, Germany.
PMID: 28892560 DOI: 10.1002/ana.25044
Abstract

Objective: Autosomal recessive primary microcephaly (MCPH) is a rare condition characterized by a reduced cerebral cortex accompanied with intellectual disability. Mutations in 17 genes have been shown to cause this phenotype. Recently, mutations in CIT, encoding CRIK (citron rho-interacting kinase)-a component of the central spindle matrix-were added. We aimed at identifying novel MCPH-associated genes and exploring their functional role in pathogenesis.

Methods: Linkage analysis and whole exome Sequencing were performed in consanguineous and nonconsanguineous MCPH families to identify disease-causing variants. Functional consequences were investigated by RNA studies and on the cellular level using immunofluorescence and microscopy.

Results: We identified homozygous mutations in KIF14 (NM_014875.2;c.263T>A;pLeu88*, c.2480_2482delTTG; p.Val827del, and c.4071G>A;p.Gln1357=) as the likely cause in 3 MCPH families. Furthermore, in a patient presenting with a severe form of primary microcephaly and short stature, we identified compound heterozygous missense mutations in KIF14 (NM_014875.2;c.2545C>G;p.His849Asp and c.3662G>T;p.Gly1221Val). Three of the 5 identified mutations impaired splicing, and 2 resulted in a truncated protein. Intriguingly, Kif14 knockout mice also showed primary microcephaly. Human kinesin-like protein KIF14, a microtubule motor protein, localizes at the midbody to finalize cytokinesis by interacting with CRIK. We found impaired localization of both KIF14 and CRIK at the midbody in patient-derived fibroblasts. Furthermore, we observed a large number of binucleated and apoptotic cells-signs of failed cytokinesis that we also observed in experimentally KIF14-depleted cells.

Interpretation: Our data corroborate the role of an impaired cytokinesis in the etiology of primary and syndromic microcephaly, as has been proposed by recent findings on CIT mutations. Ann Neurol 2017;82:562-577.