Analysis of fibroblasts from patients with cblC and cblG genetic defects of cobalamin metabolism reveals global dysregulation of alternative splicing
| Autor: | Jean-Louis Guéant, David Coelho, François Feillet, Natacha Dreumont, Ziad Hassan, Virginie Marchand, Matthias R. Baumgartner, Abderrahim Oussalah, Jean-Michel Camadro, Justine Flayac, David S. Rosenblatt, Charif Rashka, Sébastien Hergalant |
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| Přispěvatelé: | Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence des maladies héréditaires du métabolisme (MaMEA Nancy-Brabois), Institut Jacques Monod (IJM (UMR_7592)), Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Universität Zürich [Zürich] = University of Zurich (UZH), McGill University = Université McGill [Montréal, Canada], Camadro, Jean-Michel, Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Ingénierie, Biologie et Santé en Lorraine (IBSLor), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), University of Zürich [Zürich] (UZH), McGill University, Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Zurich |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Proteomics
[MATH.MATH-PR] Mathematics [math]/Probability [math.PR] MESH: Vitamin B 12 Deficiency [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] [SDV]Life Sciences [q-bio] RNA-binding protein [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase ELAV-Like Protein 1 0302 clinical medicine Gene expression Genetics (clinical) [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM] 0303 health sciences MESH: ELAV-Like Protein 1 MESH: Alternative Splicing MESH: Proteomics RNA-Binding Proteins [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular Networks [q-bio.MN] General Medicine MESH: Gene Expression Regulation 3. Good health Cell biology [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biomolecules [q-bio.BM] Vitamin B 12 Ribonucleoproteins RNA splicing MESH: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] Oxidoreductases 2716 Genetics (clinical) 610 Medicine & health Biology [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics Cell Line 03 medical and health sciences 1311 Genetics [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] 1312 Molecular Biology Genetics [SDV.BBM] Life Sciences [q-bio]/Biochemistry Molecular Biology [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology MESH: Oxidoreductases Molecular Biology Gene 030304 developmental biology Messenger RNA [INFO.INFO-DB]Computer Science [cs]/Databases [cs.DB] MESH: Humans Alternative splicing RNA Vitamin B 12 Deficiency [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology Fibroblasts MESH: Cell Line [MATH.MATH-PR]Mathematics [math]/Probability [math.PR] Alternative Splicing [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition MESH: Ribonucleoproteins MESH: RNA-Binding Proteins MESH: Vitamin B 12 Gene Expression Regulation [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular Networks [q-bio.MN] [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics 10036 Medical Clinic MESH: Fibroblasts CBLC [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics Human Molecular Genetics, Oxford University Press (OUP), 2020, 29 (12), pp.1969-1985. ⟨10.1093/hmg/ddaa027⟩ Human Molecular Genetics, 2020, 29 (12), pp.1969-1985. ⟨10.1093/hmg/ddaa027⟩ Human Molecular Genetics, Oxford University Press (OUP), 2020, ⟨10.1093/hmg/ddaa027⟩ Human Molecular Genetics, Oxford University Press (OUP), 2020, 29 (12), pp.1969-1985. ⟨10.1093/hmg/ddaa027/5739951⟩ |
| ISSN: | 0964-6906 1460-2083 |
| DOI: | 10.1093/hmg/ddaa027⟩ |
| Popis: | International audience; Vitamin B12 or cobalamin (Cbl) metabolism can be affected by genetic defects leading to defective activity of either methylmalonyl-CoA mutase or methionine synthase or both enzymes. Patients usually present with a wide spectrum of pathologies suggesting that various cellular processes could be affected by modifications in gene expression. We have previously demonstrated that these genetic defects are associated with subcellular mislocalization of RNA binding proteins and subsequent altered nucleo-cytoplasmic shuttling of mRNAs. In order to characterize the possible changes of gene expression in these diseases, we have investigated global gene expression in fibroblasts from patients with cblC and cblG inherited disorders by RNA-seq. The most differentially expressed genes are strongly associated with developmental processes, neurological, ophthalmologic and cardiovascular diseases. These associations are consistent with the clinical presentation of cblC and cblG disorders. Multivariate analysis of transcript processing revealed splicing alterations that led to dramatic changes in cytoskeleton organization, response to stress, methylation of macromolecules and RNA binding. The RNA motifs associated with this differential splicing reflected a potential role of RNA binding proteins such as HuR and HNRNPL. Proteomic analysis confirmed that mRNA processing was significantly disturbed. This study reports a dramatic alteration of gene expression in fibroblasts of patients with cblC and cblG disorders, which resulted partly from disturbed function of RNA binding proteins. These data suggest to evaluate the rescue of the mislocalization of RNA binding proteins as a potential strategy in the treatment of severe cases who are resistant to classical treatments with co-enzyme supplements. |
| Databáze: | OpenAIRE |
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