Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly
dc.contributor.author | Li, Hongda | |
dc.contributor.author | Bielas, Stephanie L. | |
dc.contributor.author | Zaki, Maha S. | |
dc.contributor.author | Ismail, Samira | |
dc.contributor.author | Farfara, Dorit | |
dc.contributor.author | Um, Kyongmi | |
dc.contributor.author | Gleeson, Joseph G. | |
dc.date.accessioned | 2019-08-13T12:10:23Z | |
dc.date.accessioned | 2019-08-13T15:57:05Z | |
dc.date.available | 2019-08-13T12:10:23Z | |
dc.date.available | 2019-08-13T15:57:05Z | |
dc.date.issued | 2016 | |
dc.identifier.issn | 0002-9297 | |
dc.identifier.issn | 1537-6605 | |
dc.identifier.uri | https://dx.doi.org/10.1016/j.ajhg.2016.07.004 | |
dc.identifier.uri | http://hdl.handle.net/11446/2448 | |
dc.description | WOS: 000381617200022 | en_US |
dc.description | PubMed ID: 27453578 | en_US |
dc.description.abstract | Cell 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.sponsorship | NIH [R01NS041537, R01NS048453, R01NS052455, P01HD070494]; Howard Hughes Medical Institute; New York Stem Cell Foundation | en_US |
dc.description.sponsorship | We thank Joseph LoTurco and Ferdinando Di Cunto for communicating unpublished results and Susan Taylor for providing suggestions on the project.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.iso | eng | en_US |
dc.publisher | CELL PRESS | en_US |
dc.identifier.doi | 10.1016/j.ajhg.2016.07.004 | en_US |
dc.rights | info:eu-repo/semantics/openAccess | en_US |
dc.title | Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly | en_US |
dc.type | article | en_US |
dc.relation.journal | AMERICAN JOURNAL OF HUMAN GENETICS | en_US |
dc.department | DBÜ | en_US |
dc.identifier.issue | 2 | en_US |
dc.identifier.volume | 99 | en_US |
dc.identifier.startpage | 501 | en_US |
dc.identifier.endpage | 510 | en_US |
dc.contributor.authorID | 0000-0001-6754-5150 | en_US |
dc.contributor.authorID | 0000-0001-7840-0002 | en_US |
dc.contributor.authorID | 0000-0003-0567-5632 | en_US |
dc.contributor.authorID | 0000-0002-3606-532X | en_US |
dc.relation.publicationcategory | Makale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı | en_US |
dc.department-temp | [Li, Hongda -- Bielas, Stephanie L. -- Farfara, Dorit -- Um, Kyongmi -- Rosti, Rasim O. -- Scott, Eric C. -- Gleeson, Joseph G.] Univ Calif San Diego, Howard Hughes Med Inst, Rady Childrens Inst Genom Med, San Diego, CA 92093 USA -- [Li, Hongda -- Bielas, Stephanie L. -- Farfara, Dorit -- Um, Kyongmi -- Rosti, Rasim O. -- Scott, Eric C. -- Gleeson, Joseph G.] Rockefeller Univ, Lab Pediat Brain Dis, New York, NY 10065 USA -- [Bielas, Stephanie L.] Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA -- [Zaki, Maha S. -- Ismail, Samira] Natl Res Ctr, Dept Clin Genet, Human Genet & Genome Res Div, Cairo 12311, Egypt -- [Tu, Shu -- Chi, Neil C.] Univ Calif San Diego, Dept Med, Div Cardiol, San Diego, CA 92093 USA -- [Gabriel, Stacey] Broad Inst MIT & Harvard, Cambridge, MA 02141 USA -- [Erson-Omay, Emine Z. -- Ercan-Sencicek, A. Gulhan -- Yasuno, Katsuhito -- Bilguvar, Kaya -- Gunel, Murat] Yale Univ, Dept Neurosurg, Yale Program Neurogenet, New Haven, CT 06510 USA -- [Erson-Omay, Emine Z. -- Ercan-Sencicek, A. Gulhan -- Yasuno, Katsuhito -- Bilguvar, Kaya -- Gunel, Murat] Yale Univ, Dept Neurobiol, New Haven, CT 06510 USA -- [Erson-Omay, Emine Z. -- Ercan-Sencicek, A. Gulhan -- Yasuno, Katsuhito -- Bilguvar, Kaya -- Gunel, Murat] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA -- [Caglayan, Ahmet Okay] Istanbul Bilim Univ, Sch Med, Dept Med Genet, TR-34394 Istanbul, Turkey -- [Kaymakcalan, Hande -- Ekici, Baris] Istanbul Bilim Univ, Dept Pediat, TR-34394 Istanbul, Turkey | en_US |
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