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

Autor: Shelagh Joss, Gabriela Soares, Alan J. Quigley, Carol Wise, Paula Carroll, Carol Anne Martin, Andrew P. Jackson, Charlotte Keith, Jennie E. Murray, Angela L. Duker, Andrea Leitch, Ahmed E. Fetit, Philippe Gautier, Michael B. Bober, Paola Vagnarelli, Louise S. Bicknell, Emma Hall, Shubha R. Phadke, João Silva, Mihail Halachev, Adeline Fluteau, Karen J. Mackenzie, Andrew J. Wood
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Zdroj: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Agência para a Sociedade do Conhecimento (UMIC)-FCT-Sociedade da Informação
instacron:RCAAP
Wood, A J & Vagnarelli, P & Jackson, A P 2016, ' Mutations in genes encoding condensin complex proteins cause microcephaly through decatenation failure at mitosis ', Genes and Development, vol. 30, no. 19, pp. 2158-2172 . https://doi.org/10.1101/gad.286351.116
DOI: 10.1101/gad.286351.116
Popis: Correction to Martin et al. available at: Genes & Development 30 (19): 2158 (http://genesdev.cshlp.org/content/31/9/953.full.pdf+html). Compaction of chromosomes is essential for accurate segregation of the genome duringmitosis. In vertebrates, two condensin complexes ensure timely chromosome condensation, sister chromatid disentanglement, and maintenance of mitotic chromosome structure. Here,we report that biallelic mutations inNCAPD2,NCAPH, orNCAPD3, 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. This work was supported by funding from the Medical Research Council, the Lister Institute for Preventative Medicine, and the European Research Council (ERC; 281847 to A.P.J.); a Biotechnology and Biological Sciences Research Council grant (BB/ K017632/1 to P.V); a Sir Henry Dale Fellowship (grant 102560/ Z/13/Z to A.J.W.); Medical Research Scotland (to L.S.B.); the Potentials Foundation (to C.A.W.); and the Indian Council of Medical Research (BMS 54/2/2013 to S.R.P). The Deciphering Developmental Disorders Study presents independent research commissioned by the Health Innovation Challenge Fund (grant no. HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant no. WT098051). The views expressed here are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83) granted by the Cambridge South Research Ethics Committee, and GEN/ 284/12 granted by the Republic of Ireland. We acknowledge the support of the National Institute for Health Research through the Comprehensive Clinical Research Network.
Databáze: OpenAIRE
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