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New insights into minor splicing-a transcriptomic analysis of cells derived from TALS patients.
RNA. 2019 09; 25(9):1130-1149.RNA

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.

Authors+Show Affiliations

INRIA Erable, CNRS LBBE UMR 5558, University Lyon 1, University of Lyon, F-69622 Villeurbanne, France. "Genetics of Neurodevelopment" Team, Lyon Neuroscience Research Centre, UMR5292 CNRS U1028 Inserm, University of Lyon, F-69500 Bron, France.INRIA Erable, CNRS LBBE UMR 5558, University Lyon 1, University of Lyon, F-69622 Villeurbanne, France. "Genetics of Neurodevelopment" Team, Lyon Neuroscience Research Centre, UMR5292 CNRS U1028 Inserm, University of Lyon, F-69500 Bron, France."Genetics of Neurodevelopment" Team, Lyon Neuroscience Research Centre, UMR5292 CNRS U1028 Inserm, University of Lyon, F-69500 Bron, France."Genetics of Neurodevelopment" Team, Lyon Neuroscience Research Centre, UMR5292 CNRS U1028 Inserm, University of Lyon, F-69500 Bron, France. Clinical Genetics Unit, Department of Genetics, Hospices Civils de Lyon, F-69500 Bron, France.INRIA Erable, CNRS LBBE UMR 5558, University Lyon 1, University of Lyon, F-69622 Villeurbanne, France. "Genetics of Neurodevelopment" Team, Lyon Neuroscience Research Centre, UMR5292 CNRS U1028 Inserm, University of Lyon, F-69500 Bron, France.Division of Medical Genetics, Nemours/Alfred I. du Pont Hospital for Children, Wilmington, Delaware 19803, USA.Department of Clinical Genetics, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands. School for Oncology and Developmental Biology, GROW, Maastricht University, 6229 ER Maastricht, The Netherlands.Department of Clinical Genetics, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands. School for Oncology and Developmental Biology, GROW, Maastricht University, 6229 ER Maastricht, The Netherlands.Genetic Department for Rare Diseases and Personalized Medicine, Clinical Division, CHU Montpellier, F-34000 Montpellier, France.Department of Genetics, Tours University Hospital, F-37000 Tours, France. UMR 1253, iBrain, Tours University, Inserm, F-37000 Tours, France.Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada. Division for Immunology and Allergy, Canadian Center for Primary Immunodeficiency, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.Université de Paris, NeuroDiderot, Inserm, F-75010 Paris, France."Genetics of Neurodevelopment" Team, Lyon Neuroscience Research Centre, UMR5292 CNRS U1028 Inserm, University of Lyon, F-69500 Bron, France."Genetics of Neurodevelopment" Team, Lyon Neuroscience Research Centre, UMR5292 CNRS U1028 Inserm, University of Lyon, F-69500 Bron, France. Clinical Genetics Unit, Department of Genetics, Hospices Civils de Lyon, F-69500 Bron, France.INRIA Erable, CNRS LBBE UMR 5558, University Lyon 1, University of Lyon, F-69622 Villeurbanne, France.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31175170

Citation

Cologne, Audric, et al. "New Insights Into Minor Splicing-a Transcriptomic Analysis of Cells Derived From TALS Patients." RNA (New York, N.Y.), vol. 25, no. 9, 2019, pp. 1130-1149.
Cologne A, Benoit-Pilven C, Besson A, et al. New insights into minor splicing-a transcriptomic analysis of cells derived from TALS patients. RNA. 2019;25(9):1130-1149.
Cologne, A., Benoit-Pilven, C., Besson, A., Putoux, A., Campan-Fournier, A., Bober, M. B., De Die-Smulders, C. E. M., Paulussen, A. D. C., Pinson, L., Toutain, A., Roifman, C. M., Leutenegger, A. L., Mazoyer, S., Edery, P., & Lacroix, V. (2019). New insights into minor splicing-a transcriptomic analysis of cells derived from TALS patients. RNA (New York, N.Y.), 25(9), 1130-1149. https://doi.org/10.1261/rna.071423.119
Cologne A, et al. New Insights Into Minor Splicing-a Transcriptomic Analysis of Cells Derived From TALS Patients. RNA. 2019;25(9):1130-1149. PubMed PMID: 31175170.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - New insights into minor splicing-a transcriptomic analysis of cells derived from TALS patients. AU - Cologne,Audric, AU - Benoit-Pilven,Clara, AU - Besson,Alicia, AU - Putoux,Audrey, AU - Campan-Fournier,Amandine, AU - Bober,Michael B, AU - De Die-Smulders,Christine E M, AU - Paulussen,Aimee D C, AU - Pinson,Lucile, AU - Toutain,Annick, AU - Roifman,Chaim M, AU - Leutenegger,Anne-Louise, AU - Mazoyer,Sylvie, AU - Edery,Patrick, AU - Lacroix,Vincent, Y1 - 2019/06/07/ PY - 2019/03/29/received PY - 2019/05/28/accepted PY - 2019/6/9/pubmed PY - 2019/11/13/medline PY - 2019/6/9/entrez KW - MOPD1 KW - RNA sequencing KW - RNU4ATAC KW - U12-type introns KW - intron retention KW - minor splicing SP - 1130 EP - 1149 JF - RNA (New York, N.Y.) JO - RNA VL - 25 IS - 9 N2 - 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. SN - 1469-9001 UR - https://www.unboundmedicine.com/medline/citation/31175170/New_insights_into_minor_splicing_a_transcriptomic_analysis_of_cells_derived_from_TALS_patients_ L2 - http://www.rnajournal.org/cgi/pmidlookup?view=long&pmid=31175170 DB - PRIME DP - Unbound Medicine ER -