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.
Highlights
Aneuploidy is the leading cause of miscarriage and congenital birth defects, and a hallmark of cancer
We identified biallelic truncating mutations in coiled-coil domain-containing 84 (CCDC84, hereafter named CENATAC, for centrosomal AT-AC splicing factor, see below) in two affected siblings with 7.3 and 8.5% aneuploid blood cells, respectively (Figs 1A and EV1)
The paternal and maternal mutations both result in the creation of novel splice sites that lead to a frameshift and the loss of the C-terminal 64 amino acids of CENATAC (Fig 1B and Appendix Fig S1)
Summary
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. 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. 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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