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Mutations of KIF14 cause primary microcephaly by impairing cytokinesis.

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.

journal_name

Ann Neurol

journal_title

Annals of neurology

authors

Moawia A,Shaheen R,Rasool S,Waseem SS,Ewida N,Budde B,Kawalia A,Motameny S,Khan K,Fatima A,Jameel M,Ullah F,Akram T,Ali Z,Abdullah U,Irshad S,Höhne W,Noegel AA,Al-Owain M,Hörtnagel K,Stöbe P,Baig SM,Nürnberg P

doi

10.1002/ana.25044

subject

Has Abstract

pub_date

2017-10-01 00:00:00

pages

562-577

issue

eissn

0364-5134

issn

1531-8249

journal_volume

pub_type

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Mutations of KIF14 cause primary microcephaly by impairing cytokinesis.