title: 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.affiliation: Howard 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.
authors.forename: Hongda
authors.initials: H
authors.lastname: Li
authors.affiliation: Howard 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; Department of Human Genetics, School of Medicine, University of Michigan, Ann Arbor, 48109 MI, USA.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Bielas
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
authors.forename: Samira
authors.initials: S
authors.lastname: Ismail
authors.affiliation: Howard 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.
authors.forename: Dorit
authors.initials: D
authors.lastname: Farfara
authors.affiliation: Howard 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.
authors.forename: Kyongmi
authors.initials: K
authors.lastname: Um
authors.affiliation: Howard 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.
authors.forename: Rasim O
authors.initials: RO
authors.lastname: Rosti
authors.affiliation: Howard 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.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Scott
authors.affiliation: Division of Cardiology, Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Tu
authors.affiliation: Division of Cardiology, Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Neil C
authors.initials: NC
authors.lastname: Chi
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.affiliation: Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, School of Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: Emine Z
authors.initials: EZ
authors.lastname: Erson-Omay
authors.affiliation: Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, School of Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: A Gulhan
authors.initials: AG
authors.lastname: Ercan-Sencicek
authors.affiliation: Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, School of Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: Katsuhito
authors.initials: K
authors.lastname: Yasuno
authors.affiliation: Department of Medical Genetics, School of Medicine, Istanbul Bilim University, Istanbul 34394, Turkey.
authors.forename: Ahmet Okay
authors.initials: AO
authors.lastname: Çağlayan
authors.affiliation: Department of Pediatrics, Istanbul Bilim University, Istanbul 34394, Turkey.
authors.forename: Hande
authors.initials: H
authors.lastname: Kaymakçalan
authors.affiliation: Department of Pediatrics, Istanbul Bilim University, Istanbul 34394, Turkey.
authors.forename: Barış
authors.initials: B
authors.lastname: Ekici
authors.affiliation: Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, School of Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilguvar
authors.affiliation: Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, School of Medicine, Yale University, New Haven, CT 06510, USA. Electronic address: murat.gunel@yale.edu.
authors.forename: Murat
authors.initials: M
authors.lastname: Gunel
authors.affiliation: Howard 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. Electronic address: jogleeson@ucsd.edu.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
mesh_terms: D000483:Alleles; D017209:Apoptosis / Q000235:genetics; D018385:Centrosome / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D048749:Cytokinesis / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology*; D008938:Mitosis / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C115635:citron-kinase; D017346:Protein Serine-Threonine Kinases