Mutations in genes encoding condensin complex proteins cause microcephaly through decatenation failure at mitosis.

Autor:	Martin CA; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom., Murray JE; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom., Carroll P; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom., Leitch A; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom., Mackenzie KJ; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom., Halachev M; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom., Fetit AE; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom., Keith C; South East Scotland Cytogenetics Service, Western General Hospital, Edinburgh EH4 2XU, United Kingdom., Bicknell LS; 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., Fluteau A; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom., Gautier P; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom., Hall EA; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom., Joss S; West of Scotland Genetic Service, Southern General Hospital, Glasgow G51 4TF, United Kingdom., Soares G; Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto, 4099-028 Porto, Portugal., Silva J; 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., Bober MB; Division of Genetics, Department of Pediatrics, A.I. duPont Hospital for Children, Wilmington, Delaware 19803, USA., Duker A; Division of Genetics, Department of Pediatrics, A.I. duPont Hospital for Children, Wilmington, Delaware 19803, USA., Wise CA; 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., Quigley AJ; Department of Radiology, Royal Hospital for Sick Children, Edinburgh EH9 1LF, United Kingdom., Phadke SR; Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India., Wood AJ; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom., Vagnarelli P; Biosciences, Research Institute for Health and Environment, Brunel University, London UB8 3PH, United Kingdom., Jackson AP; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
Jazyk:	angličtina
Zdroj:	Genes & development [Genes Dev] 2016 Oct 01; Vol. 30 (19), pp. 2158-2172. Date of Electronic Publication: 2016 Oct 13.
DOI:	10.1101/gad.286351.116
Abstrakt:	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. (© 2016 Martin et al.; Published by Cold Spring Harbor Laboratory Press.)
Databáze:	MEDLINE
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