New insights into minor splicing-a transcriptomic analysis of cells derived from TALS patients

Audric Cologne, Clara Benoit-Pilven, Alicia Besson, Audrey Putoux, Amandine Campan-Fournier, Michael B. Bober, Christine E. M. De Die-Smulders, Aimee D. C. PAULUSSEN, Lucile Pinson, Annick Toutain, Chaim M. Roifman, Anne-Louise Leutenegger, Sylvie Mazoyer*, Patrick Edery, Vincent Lacroix

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Web of Science)

Abstract

Minor intron splicing plays a central role in human embryonic development and survival. Indeed, biallelic mutations in RNU4ATAC, transcribed into the minor spliceosomal U4atac snRNA, are responsible for three rare autosomal recessive multimalformation disorders named Taybi-Linder (TALS/MOPD1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes, which associate numerous overlapping signs of varying severity. Although RNA-seq experiments have been conducted on a few RFMN patient cells, none have been performed in TALS, and more generally no in-depth transcriptomic analysis of the similar to 700 human genes containing a minor (U12-type) intron had been published as yet. We thus sequenced RNA from cells derived from five skin, three amniotic fluid, and one blood biosamples obtained from seven unrelated TALS cases and from age- and sex-matched controls. This allowed us to describe for the first time the mRNA expression and splicing profile of genes containing U12-type introns, in the context of a functional minor spliceosome. Concerning RNU4ATAC-mutated patients, we show that as expected, they display distinct U12-type intron splicing profiles compared to controls, but that rather unexpectedly mRNA expression levels are mostly unchanged. Furthermore, although U12-type intron missplicing concerns most of the expressed U12 genes, the level of U12-type intron retention is surprisingly low in fibroblasts and amniocytes, and much more pronounced in blood cells. Interestingly, we found several occurrences of introns that can be spliced using either U2, U12, or a combination of both types of splice site consensus sequences, with a shift towards splicing using preferentially U2 sites in TALS patients' cells compared to controls.

Original languageEnglish
Pages (from-to)1130-1149
Number of pages20
JournalRna-A Publication of the Rna Society
Volume25
Issue number9
DOIs
Publication statusPublished - Sep 2019

Keywords

  • MOPD1
  • RNU4ATAC
  • minor splicing
  • U12-type introns
  • RNA sequencing
  • intron retention
  • MESSENGER-RNA
  • INTRON RETENTION
  • DEVELOPMENTAL DISORDER
  • U12-DEPENDENT INTRONS
  • U12-TYPE INTRONS
  • MUTATIONS
  • SPLICEOSOME
  • COMPONENT
  • TWINTRON

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