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

Genes Dev. 2016 Oct 1;30(19):2158-2172. doi: 10.1101/gad.286351.116.

Carol-Anne Martin ¹, Jennie E Murray ¹, Paula Carroll ¹, Andrea Leitch ¹, Karen J Mackenzie ¹, Mihail Halachev ¹, Ahmed E Fetit ¹, Charlotte Keith ², Louise S Bicknell ¹ ³, Adeline Fluteau ¹, Philippe Gautier ¹, Emma A Hall ¹, Shelagh Joss ⁴, Gabriela Soares ⁵, João Silva ⁶ ⁷, Michael B Bober ⁸, Angela Duker ⁸, Carol A Wise ⁹ ¹⁰ ¹¹ ¹², Alan J Quigley ¹³, Shubha R Phadke ¹⁴, Deciphering Developmental Disorders Study, Andrew J Wood ¹, Paola Vagnarelli ¹⁵, Andrew P Jackson ¹

Affiliations

1 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
2 South East Scotland Cytogenetics Service, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
3 Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
4 West of Scotland Genetic Service, Southern General Hospital, Glasgow G51 4TF, United Kingdom.
5 Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto, 4099-028 Porto, Portugal.
6 Instituto de Biologia Molecular e Celular (IBMC), 4150 Porto, Portugal.
7 Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, 4200-135 Porto, Portugal.
8 Division of Genetics, Department of Pediatrics, A.I. duPont Hospital for Children, Wilmington, Delaware 19803, USA.
9 Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA.
10 Department of Orthopedic Surgery, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA.
11 Department of Pediatrics, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA.
12 McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas 75350, USA.
13 Department of Radiology, Royal Hospital for Sick Children, Edinburgh EH9 1LF, United Kingdom.
14 Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India.
15 Biosciences, Research Institute for Health and Environment, Brunel University, London UB8 3PH, United Kingdom.

PMID: 27737959 DOI: 10.1101/gad.286351.116

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

condensin; decatenation; microcephaly; neurodevelopment.

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