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

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.

• Authors: Hongda Li, Stephanie L Bielas, Maha S Zaki, Samira Ismail, Dorit Farfara, Kyongmi Um, Rasim O Rosti, Eric C Scott, Shu Tu, Neil C Chi, Stacey Gabriel, Emine Z Erson-Omay, A Gulhan Ercan-Sencicek, Katsuhito Yasuno, Ahmet Okay Çağlayan, Hande Kaymakçalan, Barış Ekici, Kaya Bilguvar, Murat Gunel, Joseph G Gleeson
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 99 Issue 2 Pg. 501-10 (Aug 04 2016) ISSN: 1537-6605 [Electronic] United States
• PMID: 27453578 (Publication Type: Case Reports, Journal Article)
• Copyright: Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Intracellular Signaling Peptides and Proteins
• citron-kinase
• Protein Serine-Threonine Kinases

Topics

• Alleles
• Apoptosis (genetics)
• Centrosome (metabolism)
• Child
• Child, Preschool
• Cytokinesis (genetics)
• Female
• Genes, Recessive
• Humans
• Infant, Newborn
• Intracellular Signaling Peptides and Proteins (genetics)
• Male
• Microcephaly (genetics, pathology)
• Mitosis (genetics)
• Mutation, Missense (genetics)
• Pedigree
• Protein Serine-Threonine Kinases (genetics)