Mutations in genes encoding condensin complex proteins cause microcephaly through decatenation failure at mitosis
- Carol-Anne Martin1,17,
- Jennie E. Murray1,17,
- Paula Carroll1,
- Andrea Leitch1,
- Karen J. Mackenzie1,
- Mihail Halachev1,
- Ahmed E. Fetit1,
- Charlotte Keith2,
- Louise S. Bicknell1,3,
- Adeline Fluteau1,
- Philippe Gautier1,
- Emma A. Hall1,
- Shelagh Joss4,
- Gabriela Soares5,
- João Silva6,7,
- Michael B. Bober8,
- Angela Duker8,
- Carol A. Wise9,10,11,12,
- Alan J. Quigley13,
- Shubha R. Phadke14,
- The Deciphering Developmental Disorders Study15,
- Andrew J. Wood1,
- Paola Vagnarelli16 and
- Andrew P. Jackson1
- 1MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom;
- 2South East Scotland Cytogenetics Service, Western General Hospital, Edinburgh EH4 2XU, United Kingdom;
- 3Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand;
- 4West of Scotland Genetic Service, Southern General Hospital, Glasgow G51 4TF, United Kingdom;
- 5Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto, 4099-028 Porto, Portugal;
- 6Instituto de Biologia Molecular e Celular (IBMC), 4150 Porto, Portugal;
- 7Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, 4200-135 Porto, Portugal;
- 8Division of Genetics, Department of Pediatrics, A.I. duPont Hospital for Children, Wilmington, Delaware 19803, USA;
- 9Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA;
- 10Department of Orthopedic Surgery, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA;
- 11Department of Pediatrics, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA;
- 12McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas 75350, USA;
- 13Department of Radiology, Royal Hospital for Sick Children, Edinburgh EH9 1LF, United Kingdom;
- 14Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India;
- 15Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
- 16Biosciences, Research Institute for Health and Environment, Brunel University, London UB8 3PH, United Kingdom
- Corresponding author: andrew.jackson{at}igmm.ed.ac.uk
-
↵17 These authors contributed equally to this work.
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.
Keywords
Footnotes
-
Supplemental material is available for this article.
-
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.286351.116.
- Received June 29, 2016.
- Accepted September 9, 2016.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
