@article{910894c3ba18495a8a88663cbe35eafe,
title = "Chromosomal instability by mutations in the novel minor spliceosome component CENATAC",
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 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.",
keywords = "aneuploidy, CCDC84, CENATAC, minor spliceosome",
author = "{de Wolf}, Bas and Ali Oghabian and Akinyi, {Maureen V.} and Sandra Hanks and Tromer, {Eelco C.} and {van Hooff}, {Jolien J.E.} and {van Voorthuijsen}, Lisa and {van Rooijen}, {Laura E.} and Jens Verbeeren and Uijttewaal, {Esther C.H.} and Baltissen, {Marijke P.A.} and Shawn Yost and Philippe Piloquet and Michiel Vermeulen and Berend Snel and Bertrand Isidor and Nazneen Rahman and Frilander, {Mikko J.} and Kops, {Geert J.P.L.}",
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 Jus{\'e}lius 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 Jus{\'e}lius 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: {\textcopyright} 2021 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2021",
month = jul,
day = "15",
doi = "10.15252/embj.2020106536",
language = "English",
volume = "40",
pages = "1--18",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "14",
}