Moawia, Abubakar, Shaheen, Ranad, Rasool, Sajida, Waseem, Syeda Seema, Ewida, Nour, Budde, Birgit, Kawalia, Amit, Motameny, Susanne, Khan, Kamal, Fatima, Ambrin, Jameel, Muhammad, Ullah, Farid, Akram, Talia, Ali, Zafar, Abdullah, Uzma, Irshad, Saba, Hoehne, Wolfgang, Noegel, Angelika Anna, Al-Owain, Mohammed, Hoertnagel, Konstanze, Stoebe, Petra, Baig, Shahid Mahmood, Nuernberg, Peter, Alkuraya, Fowzan Sami, Hahn, Andreas and Hussain, Muhammad Sajid ORCID: 0000-0002-1353-8809 (2017). Mutations of KIF14 cause primary microcephaly by impairing cytokinesis. Ann. Neurol., 82 (4). S. 562 - 578. HOBOKEN: WILEY. ISSN 1531-8249

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Abstract

ObjectiveAutosomal 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 matrixwere added. We aimed at identifying novel MCPH-associated genes and exploring their functional role in pathogenesis. MethodsLinkage 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. ResultsWe 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 cellssigns of failed cytokinesis that we also observed in experimentally KIF14-depleted cells. InterpretationOur 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

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Moawia, AbubakarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shaheen, RanadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rasool, SajidaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waseem, Syeda SeemaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ewida, NourUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Budde, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kawalia, AmitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Motameny, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khan, KamalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fatima, AmbrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jameel, MuhammadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ullah, FaridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Akram, TaliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ali, ZafarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abdullah, UzmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Irshad, SabaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoehne, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noegel, Angelika AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Al-Owain, MohammedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoertnagel, KonstanzeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoebe, PetraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baig, Shahid MahmoodUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alkuraya, Fowzan SamiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hahn, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hussain, Muhammad SajidUNSPECIFIEDorcid.org/0000-0002-1353-8809UNSPECIFIED
URN: urn:nbn:de:hbz:38-215179
DOI: 10.1002/ana.25044
Journal or Publication Title: Ann. Neurol.
Volume: 82
Number: 4
Page Range: S. 562 - 578
Date: 2017
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1531-8249
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
KINASE; GENE; PROTEINS; FAMILY; DOMAIN; CITMultiple languages
Clinical Neurology; NeurosciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21517

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