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

  1. Vincent Lacroix1,13
  1. 1INRIA Erable, CNRS LBBE UMR 5558, University Lyon 1, University of Lyon, F-69622 Villeurbanne, France
  2. 2“Genetics of Neurodevelopment” Team, Lyon Neuroscience Research Centre, UMR5292 CNRS U1028 Inserm, University of Lyon, F-69500 Bron, France
  3. 3Clinical Genetics Unit, Department of Genetics, Hospices Civils de Lyon, F-69500 Bron, France
  4. 4Division of Medical Genetics, Nemours/Alfred I. du Pont Hospital for Children, Wilmington, Delaware 19803, USA
  5. 5Department of Clinical Genetics, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands
  6. 6School for Oncology and Developmental Biology, GROW, Maastricht University, 6229 ER Maastricht, The Netherlands
  7. 7Genetic Department for Rare Diseases and Personalized Medicine, Clinical Division, CHU Montpellier, F-34000 Montpellier, France
  8. 8Department of Genetics, Tours University Hospital, F-37000 Tours, France
  9. 9UMR 1253, iBrain, Tours University, Inserm, F-37000 Tours, France
  10. 10Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada
  11. 11Division for Immunology and Allergy, Canadian Center for Primary Immunodeficiency, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
  12. 12Université de Paris, NeuroDiderot, Inserm, F-75010 Paris, France
  1. Corresponding author: sylvie.mazoyer{at}inserm.fr
  1. 13 These authors contributed equally to this work.

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 ∼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.

Keywords

Footnotes

  • Received March 29, 2019.
  • Accepted May 28, 2019.

This article, published in RNA, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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  1. RNA 25: 1130-1149 © 2019 Cologne et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society

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