Moawia A1,2,3, Shaheen R4, Rasool S1,5, Waseem SS1,2,3, 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 AA1,2,6,7, Al-Owain M8, Hörtnagel K9, Stöbe P9, Baig SM3, Nürnberg P1,6,7, Alkuraya FS4,10, Hahn A11, Hussain MS1,2,6.
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.
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.
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.
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.
Zur Journal of Annals of Neurology Publikation
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- Cologne Center for Genomics, University of Cologne, Cologne, Germany.
- Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.
- Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering, Pakistan Institute of Engineering and Applied Sciences, Faisalabad, Pakistan.
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
- Institute of Biochemistry and Biotechnology, Quaid-e-Azam Campus, University of the Punjab, Lahore, Pakistan.
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
- Department of Medical Genetics, King Faisal Specialist Hospital, Riyadh, Saudi Arabia.
- Center for Genomics and Transcriptomics, Tübingen, Germany.
- Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
- Department of Child Neurology, University of Giessen, Giessen, Germany.