Chromosomal instability by mutations in the novel minor spliceosome component CENATAC. (19th May 2021)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: EMBO journal. Volume 40:Number 14(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-05-19
• Subjects: aneuploidy -- CCDC84 -- CENATAC -- minor spliceosome; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2020106536
• Languages: English
• ISSNs: 0261-4189

Abstract

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. SYNOPSIS: Genetic causes of aneuploidy in humans remain largely unknown. Here, patient exome sequencing reveals pathogenic patient mutations in CENATAC/CCDC84, encoding a novel component of the minor spliceosome, and downstream effects on chromosome segregation in mitosis. Pathogenic mutations in CENATAC were identified in two siblings with Mosaic Variegated Aneuploidy syndrome. CENATAC is a novel component of the minor (U12‐dependent) spliceosome di‐ and tri‐snRNP complexes. CENATAC malfunction leads to defective splicing of minor introns characterized by reduced intrinsic splicing activity, predominantly those with AT‐AN splice sites. CENATAC malfunction leads to defective chromosome congression in mitosis. CENATAC's mitotic phenotype is a secondary effect of defective minor spliceosome function. Abstract : Biallelic CCDC84/CENATAC mutations identified through patient exome sequencing link altered minor intron splicing to constitutional mosaic aneuploidy in humans.