Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly
Hongda Li1, Stephanie L Bielas2, Maha S Zaki3
1Howard Hughes Medical Institute, Rady Children's Institute of Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA; Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, NY 10065, USA.
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.
Insights
Mutations in the CIT gene impairing citron rho-interacting kinase (CIT) activity cause primary microcephaly (MCPH) by disrupting cell division. This highlights the critical role of cytokinesis in neurodevelopmental disorders.
Area of Science:
- Genetics
- Neurobiology
- Cell Biology
Background:
- Autosomal-recessive primary microcephaly (MCPH) is a neurodevelopmental disorder linked to mutations in genes affecting centrosome function.
- The precise mechanisms underlying MCPH etiology remain incompletely understood due to the multifaceted roles of centrosomes.
Observation:
- Three families presented with homozygous missense mutations in the CIT gene, encoding citron rho-interacting kinase (CIT).
- These mutations altered conserved amino acid residues within the kinase domain, leading to impaired kinase activity.
Findings:
- Neural progenitor cells derived from MCPH patients exhibited defective cytokinesis, characterized by delayed mitosis, multipolar spindles, and elevated apoptosis.
- These cellular defects were successfully rescued using CRISPR/Cas9 genome editing, confirming the causative role of CIT mutations.
Implications:
- This study identifies mutations in CIT as a novel cause of primary microcephaly.
- The findings underscore the crucial role of proper cytokinesis, regulated by CIT, in human brain development and MCPH pathogenesis.
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