Chromosomal instability by mutations in the novel minor spliceosome component CENATAC
de Wolf, Bas; Oghabian, Ali; Akinyi, Maureen V.; Hanks, Sandra; Tromer, Eelco C.; van Hooff, Jolien J.E.; van Voorthuijsen, Lisa; van Rooijen, Laura E.; Verbeeren, Jens; Uijttewaal, Esther C.H.; Baltissen, Marijke P.A.; Yost, Shawn; Piloquet, Philippe; Vermeulen, Michiel; Snel, Berend; Isidor, Bertrand; Rahman, Nazneen; Frilander, Mikko J.; Kops, Geert J.P.L.
(2021) EMBO Journal, volume 40, issue 14, pp. 1 - 18
(Article)
Abstract
Aneuploidy is the leading cause of miscarriage and congenital birth defects, and a hallmark of cancer. Despite this strong association with human disease, the genetic causes of aneuploidy remain largely unknown. Through exome sequencing of patients with constitutional mosaic aneuploidy, we identified biallelic truncating mutations in CENATAC (CCDC84). We show
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that CENATAC is a novel component of the minor (U12-dependent) spliceosome that promotes splicing of a specific, rare minor intron subtype. This subtype is characterized by AT-AN splice sites and relatively high basal levels of intron retention. CENATAC depletion or expression of disease mutants resulted in excessive retention of AT-AN minor introns in ~ 100 genes enriched for nucleocytoplasmic transport and cell cycle regulators, and caused chromosome segregation errors. Our findings reveal selectivity in minor intron splicing and suggest a link between minor spliceosome defects and constitutional aneuploidy in humans.
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Keywords: aneuploidy, CCDC84, CENATAC, minor spliceosome, General Biochemistry,Genetics and Molecular Biology, General Immunology and Microbiology, Molecular Biology, General Neuroscience, Journal Article
ISSN: 0261-4189
Publisher: Nature Publishing Group
Note: Funding Information: We thank the patient family members for their participation in this study. We thank Anna Zachariou for assistance with recruitment, Emma Ramsay for performing the exome sequencing, and Elise Ruark for discussions about the analyses. We thank the Kops, Frilander, Snel, and Rahman laboratories for discussions and comments on the manuscript. We thank Andrew Holland for reagents. The Kops and Vermeulen labs are part of the Oncode Institute, which is partly funded by KWF Kankerbestrijding (DCS). This study was further funded by the Dutch Research Council (NWO) (OCENW.KLEIN.182), the Cancer Genomics Center (CGC.nl), the Wellcome Trust (100210/Z/12/Z) to NR, Sigrid Jusélius Foundation (MF), Jane and Aatos Erkko Foundation (MF), Academy of Finland grant 1308657 (MF), and a Postdoctoral Research Fellowship by the Herchel Smith Fund at the University of Cambridge (ET). Funding Information: We thank the patient family members for their participation in this study. We thank Anna Zachariou for assistance with recruitment, Emma Ramsay for performing the exome sequencing, and Elise Ruark for discussions about the analyses. We thank the Kops, Frilander, Snel, and Rahman laboratories for discussions and comments on the manuscript. We thank Andrew Holland for reagents. The Kops and Vermeulen labs are part of the Oncode Institute, which is partly funded by KWF Kankerbestrijding (DCS). This study was further funded by the Dutch Research Council (NWO) (OCENW.KLEIN.182), the Cancer Genomics Center (CGC.nl), the Wellcome Trust (100210/Z/12/Z) to NR, Sigrid Jusélius Foundation (MF), Jane and Aatos Erkko Foundation (MF), Academy of Finland grant 1308657 (MF), and a Postdoctoral Research Fellowship by the Herchel Smith Fund at the University of Cambridge (ET). Publisher Copyright: © 2021 The Authors. Published under the terms of the CC BY 4.0 license
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