title: Mutations in genes encoding condensin complex proteins cause microcephaly through decatenation failure at mitosis.
abstract: Compaction of chromosomes is essential for accurate segregation of the genome during mitosis. In vertebrates, two condensin complexes ensure timely chromosome condensation, sister chromatid disentanglement, and maintenance of mitotic chromosome structure. Here, we report that biallelic mutations in NCAPD2, NCAPH, or NCAPD3, encoding subunits of these complexes, cause microcephaly. In addition, hypomorphic Ncaph2 mice have significantly reduced brain size, with frequent anaphase chromatin bridge formation observed in apical neural progenitors during neurogenesis. Such DNA bridges also arise in condensin-deficient patient cells, where they are the consequence of failed sister chromatid disentanglement during chromosome compaction. This results in chromosome segregation errors, leading to micronucleus formation and increased aneuploidy in daughter cells. These findings establish "condensinopathies" as microcephalic disorders, with decatenation failure as an additional disease mechanism for microcephaly, implicating mitotic chromosome condensation as a key process ensuring mammalian cerebral cortex size.
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Carol-Anne
authors.initials: CA
authors.lastname: Martin
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Jennie E
authors.initials: JE
authors.lastname: Murray
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Paula
authors.initials: P
authors.lastname: Carroll
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Leitch
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Mackenzie
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Mihail
authors.initials: M
authors.lastname: Halachev
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Ahmed E
authors.initials: AE
authors.lastname: Fetit
authors.affiliation: South East Scotland Cytogenetics Service, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Keith
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.|Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
authors.forename: Louise S
authors.initials: LS
authors.lastname: Bicknell
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Adeline
authors.initials: A
authors.lastname: Fluteau
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gautier
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Emma A
authors.initials: EA
authors.lastname: Hall
authors.affiliation: West of Scotland Genetic Service, Southern General Hospital, Glasgow G51 4TF, United Kingdom.
authors.forename: Shelagh
authors.initials: S
authors.lastname: Joss
authors.affiliation: Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto, 4099-028 Porto, Portugal.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Soares
authors.affiliation: Instituto de Biologia Molecular e Celular (IBMC), 4150 Porto, Portugal.|Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, 4200-135 Porto, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Silva
authors.affiliation: Division of Genetics, Department of Pediatrics, A.I. duPont Hospital for Children, Wilmington, Delaware 19803, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Bober
authors.affiliation: Division of Genetics, Department of Pediatrics, A.I. duPont Hospital for Children, Wilmington, Delaware 19803, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Duker
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA.|Department of Orthopedic Surgery, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA.|Department of Pediatrics, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA.|McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas 75350, USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wise
authors.affiliation: Department of Radiology, Royal Hospital for Sick Children, Edinburgh EH9 1LF, United Kingdom.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Quigley
authors.affiliation: Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India.
authors.forename: Shubha R
authors.initials: SR
authors.lastname: Phadke
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wood
authors.affiliation: Biosciences, Research Institute for Health and Environment, Brunel University, London UB8 3PH, United Kingdom.
authors.forename: Paola
authors.initials: P
authors.lastname: Vagnarelli
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000782:Aneuploidy; D000818:Animals; D043863:Catenanes / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D043171:Chromosomal Instability / Q000235:genetics; D020090:Chromosome Segregation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008831:Microcephaly / Q000235:genetics*; D048629:Micronuclei, Chromosome-Defective; D008938:Mitosis / Q000235:genetics*; D046912:Multiprotein Complexes / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells
chemical_list: D043863:Catenanes; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; C572282:Ncaph2 protein, mouse; D009687:Nuclear Proteins; C108312:condensin complexes; D000251:Adenosine Triphosphatases
keywords: condensin; decatenation; microcephaly; neurodevelopment