1. Chromosomal instability by mutations in the novel minor spliceosome component CENATAC.
- Author
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de Wolf B, Oghabian A, Akinyi MV, Hanks S, Tromer EC, van Hooff JJE, van Voorthuijsen L, van Rooijen LE, Verbeeren J, Uijttewaal ECH, Baltissen MPA, Yost S, Piloquet P, Vermeulen M, Snel B, Isidor B, Rahman N, Frilander MJ, and Kops GJPL
- Subjects
- Amino Acid Sequence, Cell Cycle genetics, Cell Line, Cell Line, Tumor, HeLa Cells, Humans, Introns genetics, Chromosomal Instability genetics, Chromosomes genetics, Mutation genetics, Spliceosomes genetics
- 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., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2021
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