Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly.

TitleBiallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly.
Publication TypeJournal Article
Year of Publication2016
AuthorsLi, H, Bielas, SL, Zaki, MS, Ismail, S, Farfara, D, Um, K, Rosti, RO, Scott, EC, Tu, S, Chi, NC, Gabriel, S, Erson-Omay, EZ, A Ercan-Sencicek, G, Yasuno, K, Çağlayan, AOkay, Kaymakçalan, H, Ekici, B, Bilguvar, K, Günel, M, Gleeson, JG
JournalAm J Hum Genet
Volume99
Issue2
Pagination501-10
Date Published2016 Aug 04
ISSN1537-6605
Abstract

Cell division terminates with cytokinesis and cellular separation. Autosomal-recessive primary microcephaly (MCPH) 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.

DOI10.1016/j.ajhg.2016.07.004
Alternate JournalAm. J. Hum. Genet.
PubMed ID27453578
PubMed Central IDPMC4974110
Grant ListU54 HG003067 / HG / NHGRI NIH HHS / United States
R01 NS041537 / NS / NINDS NIH HHS / United States
R01 NS048453 / NS / NINDS NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
R01 NS052455 / NS / NINDS NIH HHS / United States
P01 HD070494 / HD / NICHD NIH HHS / United States