2. Academic Validation
  3. Mutations of KIF14 cause primary microcephaly by impairing cytokinesis

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

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.

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