Mutations of KIF14 Cause Primary Microcephaly by Impairing Cytokinesis.

Moawia A^1,2,3, Shaheen R⁴, Rasool S^1,5, Waseem SS^1,2,3, Ewida N⁴, Budde B¹, Kawalia A¹, Motameny S¹, Khan K³, Fatima A³, Jameel M³, Ullah F³, Akram T³, Ali Z³, Abdullah U³, Irshad S⁵, Höhne W¹, Noegel AA^1,2,6,7, Al-Owain M⁸, Hörtnagel K⁹, Stöbe P⁹, Baig SM³, Nürnberg P^1,6,7, Alkuraya FS^4,10, Hahn A¹¹, Hussain MS^1,2,6.

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.