1. Mutations in genes encoding condensin complex proteins cause microcephaly through decatenation failure at mitosis.
- Author
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Martin CA, Murray JE, Carroll P, Leitch A, Mackenzie KJ, Halachev M, Fetit AE, Keith C, Bicknell LS, Fluteau A, Gautier P, Hall EA, Joss S, Soares G, Silva J, Bober MB, Duker A, Wise CA, Quigley AJ, Phadke SR, Wood AJ, Vagnarelli P, and Jackson AP
- Subjects
- Aneuploidy, Animals, Catenanes metabolism, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cells, Cultured, Chromosomal Instability genetics, Chromosome Segregation genetics, Female, Humans, Male, Mice, Mice, Inbred C57BL, Micronuclei, Chromosome-Defective, Neurons pathology, Nuclear Proteins genetics, Nuclear Proteins metabolism, Stem Cells, Adenosine Triphosphatases genetics, DNA-Binding Proteins genetics, Microcephaly genetics, Mitosis genetics, Multiprotein Complexes genetics, Mutation genetics
- 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., (© 2016 Martin et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2016
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