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dc.contributor.authorLi, Hongda
dc.contributor.authorBielas, Stephanie L.
dc.contributor.authorZaki, Maha S.
dc.contributor.authorIsmail, Samira
dc.contributor.authorFarfara, Dorit
dc.contributor.authorUm, Kyongmi
dc.contributor.authorGleeson, Joseph G.
dc.date.accessioned2019-08-13T12:10:23Z
dc.date.accessioned2019-08-13T15:57:05Z
dc.date.available2019-08-13T12:10:23Z
dc.date.available2019-08-13T15:57:05Z
dc.date.issued2016
dc.identifier.issn0002-9297
dc.identifier.issn1537-6605
dc.identifier.urihttps://dx.doi.org/10.1016/j.ajhg.2016.07.004
dc.identifier.urihttp://hdl.handle.net/11446/2448
dc.descriptionWOS: 000381617200022en_US
dc.descriptionPubMed ID: 27453578en_US
dc.description.abstractCell division terminates with cytokinesis and cellular separation. Autosomal-recessive primary microcephaly (PMCPH) is a neurodevelopmental disorder characterized by a reduction in brain and head size at birth in addition to non-progressive intellectual disability. MCPH is genetically heterogeneous, and 16 loci are known to be associated with loss-of-function mutations predominantly affecting centrosomal-associated proteins, but the multiple roles of centrosomes in cellular function has left questions about etiology. Here, we identified three families affected by homozygous missense mutations in CIT, encoding citron rho-interacting kinase (CIT), which has established roles in cytokinesis. All mutations caused substitution of conserved amino acid residues in the kinase domain and impaired kinase activity. Neural progenitors that were differentiated from induced pluripotent stem cells (iPSCs) derived from individuals with these mutations exhibited abnormal cytokinesis with delayed mitosis, multipolar spindles, and increased apoptosis, rescued by CRISPR/Cas9 genome editing. Our results highlight the importance of cytokinesis in the pathology of primary microcephaly.en_US
dc.description.sponsorshipNIH [R01NS041537, R01NS048453, R01NS052455, P01HD070494]; Howard Hughes Medical Institute; New York Stem Cell Foundationen_US
dc.description.sponsorshipWe thank Joseph LoTurco and Ferdinando Di Cunto for communicating unpublished results and Susan Taylor for providing suggestions on the project. We thank the subjects and their families for their contributions to this study. This work was supported by the NIH (R01NS041537, R01NS048453, R01NS052455, and P01HD070494 to N.C.), the Howard Hughes Medical Institute (J.G.G.), and the Druckenmiller Fellowship from the New York Stem Cell Foundation (to H.L). We thank the Broad Institute (U54HG003067 to E. Lander) and the Yale Center for Mendelian Disorders (U54HG006504 to R. Lifton) for sequencing support.en_US
dc.language.isoengen_US
dc.publisherCELL PRESSen_US
dc.relation.isversionof10.1016/j.ajhg.2016.07.004en_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.titleBiallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephalyen_US
dc.typearticleen_US
dc.relation.journalAMERICAN JOURNAL OF HUMAN GENETICSen_US
dc.contributor.departmentDBÜen_US
dc.identifier.issue2en_US
dc.identifier.volume99en_US
dc.identifier.startpage501en_US
dc.identifier.endpage510en_US
dc.contributor.authorID0000-0001-6754-5150en_US
dc.contributor.authorID0000-0001-7840-0002en_US
dc.contributor.authorID0000-0003-0567-5632en_US
dc.contributor.authorID0000-0002-3606-532Xen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US


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