2. Academic Validation
  3. Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

  • EMBO J. 2021 Jul 15;40(14):e106536. doi: 10.15252/embj.2020106536.
Bas de Wolf 1,  Ali Oghabian 2,  Maureen V Akinyi 2,  Sandra Hanks 3,  Eelco C Tromer 1 4,  Jolien J E van Hooff 1 4,  Lisa van Voorthuijsen 5,  Laura E van Rooijen 4,  Jens Verbeeren 2,  Esther C H Uijttewaal 1,  Marijke P A Baltissen 5,  Shawn Yost 3,  Philippe Piloquet 6,  Michiel Vermeulen 5,  Berend Snel 4,  Bertrand Isidor 6,  Nazneen Rahman 3,  Mikko J Frilander 2,  Geert J P L Kops 1
Affiliations

Affiliations

  • 1 Oncode Institute, Hubrecht Institute - Royal Academy of Arts and Sciences and University Medical Centre Utrecht, Utrecht, The Netherlands.
  • 2 Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
  • 3 Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
  • 4 Theoretical Biology and Bioinformatics, Biology, Science Faculty, Utrecht University, Utrecht, The Netherlands.
  • 5 Oncode Institute, Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Science, Radboud University Nijmegen, Nijmegen, The Netherlands.
  • 6 Service de Génétique Médicale, Unité de génétique Clinique, CHU Hotel Dieu, Nantes Cedex, France.
PMID: 34009673 DOI: 10.15252/embj.2020106536
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

CCDC84; CENATAC; aneuploidy; minor spliceosome.

Figures