Mutations of KIF14 cause primary microcephaly by impairing cytokinesis

Ann Neurol. 2017 Oct;82(4):562-577. doi: 10.1002/ana.25044. Epub 2017 Oct 14.


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.

MeSH terms

  • Caspase 7 / metabolism
  • Cell Movement / genetics
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Cytokinesis / genetics*
  • Family Health
  • Female
  • Fibroblasts / physiology
  • Gene Expression Regulation / genetics*
  • Genome-Wide Association Study
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kinesins / genetics*
  • Male
  • Microcephaly / diagnostic imaging
  • Microcephaly / genetics*
  • Microcephaly / pathology
  • Mutation / genetics*
  • Oncogene Proteins / genetics*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Tubulin / metabolism


  • Intracellular Signaling Peptides and Proteins
  • Oncogene Proteins
  • Tubulin
  • citron-kinase
  • Protein Serine-Threonine Kinases
  • CASP7 protein, human
  • Caspase 7
  • KIF14 protein, human
  • Kinesins