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
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
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