A conserved splicing mechanism of the LMNA gene controls premature aging
| العنوان: | A conserved splicing mechanism of the LMNA gene controls premature aging |
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| المؤلفون: | Jamal Tazi, Isabelle Behm-Ansmant, José M.P. Freije, Claire Navarro, James Stévenin, Annachiara De Sandre-Giovannoli, Fernando G. Osorio, Isabel C. Lopez-Mejia, Cyril F. Bourgeois, Christiane Branlant, Nicolas Lévy, Carlos López-Otín, Valentin Vautrot, Marion de Toledo |
| المساهمون: | Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Maturation des ARN et enzymologie moléculaire (MAEM), Cancéropôle du Grand Est-Université Henri Poincaré - Nancy 1 (UHP)-IFR111-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de la Méditerranée - Aix-Marseille 2, Universidad de Oviedo [Oviedo], Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), de Toledo, Marion |
| المصدر: | Human Molecular Genetics Human Molecular Genetics, Oxford University Press (OUP), 2011, 20 (23), pp.4540-4555. ⟨10.1093/hmg/ddr385⟩ Human Molecular Genetics, 2011, 20 (23), pp.4540-4555. ⟨10.1093/hmg/ddr385⟩ RUO. Repositorio Institucional de la Universidad de Oviedo instname Human Molecular Genetics, Oxford University Press (OUP), 2011, 20 (23), pp.4540--55. ⟨10.1093/hmg/ddr385⟩ |
| بيانات النشر: | Oxford University Press (OUP), 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Aging, [SDV]Life Sciences [q-bio], [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], LMNA, Mice, Exon, Progeria, 0302 clinical medicine, Protein Isoforms, Cells, Cultured, Conserved Sequence, Genetics (clinical), Genetics, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Serine-Arginine Splicing Factors, integumentary system, Nuclear Proteins, RNA-Binding Proteins, Aging, Premature, Exons, General Medicine, Lamin Type A, Progerin, [SDV] Life Sciences [q-bio], [SDV.IMM]Life Sciences [q-bio]/Immunology, Premature aging, Silent mutation, Premature/*genetics Animals Base Sequence Cells, congenital, hereditary, and neonatal diseases and abnormalities, [SDV.IMM] Life Sciences [q-bio]/Immunology, RNA Splicing, Molecular Sequence Data, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Transfection, Cultured Conserved Sequence/genetics *Evolution, Evolution, Molecular, 03 medical and health sciences, Splicing factor, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein Precursors, Molecular Biology, Molecular Exons/genetics Fibroblasts/metabolism/pathology Humans Lamin Type A/*genetics Mice Molecular Sequence Data Nuclear Proteins/genetics/metabolism Nucleic Acid Conformation Progeria/genetics/pathology Protein Isoforms/genetics Protein Precursors/genetics RNA/chemistry/genetics RNA Splice Sites/genetics RNA Splicing/*genetics RNA-Binding Proteins/metabolism Repressor Proteins/metabolism Transfection, 030304 developmental biology, Phenocopy, Base Sequence, nutritional and metabolic diseases, Fibroblasts, medicine.disease, Aging, Cultured Conserved Sequence/genetics *Evolution, Molecular Exons/genetics Fibroblasts/metabolism/pathology Humans Lamin Type A/*genetics Mice Molecular Sequence Data Nuclear Proteins/genetics/metabolism Nucleic Acid Conformation Progeria/genetics/pathology Protein Isoforms/genetics Protein Precursors/genetics RNA/chemistry/genetics RNA Splice Sites/genetics RNA Splicing/*genetics RNA-Binding Proteins/metabolism Repressor Proteins/metabolism Transfection, Premature/*genetics Animals Base Sequence Cells, Repressor Proteins, Nucleic Acid Conformation, RNA, RNA Splice Sites, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery |
| الوصف: | International audience; Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder phenotypically characterized by many features of premature aging. Most cases of HGPS are due to a heterozygous silent mutation (c.1824C\textgreaterT; p.Gly608Gly) that enhances the use of an internal 5' splice site (5'SS) in exon 11 of the LMNA pre-mRNA and leads to the production of a truncated protein (progerin) with a dominant negative effect. Here we show that HGPS mutation changes the accessibility of the 5'SS of LMNA exon 11 which is sequestered in a conserved RNA structure. Our results also reveal a regulatory role of a subset of serine-arginine (SR)-rich proteins, including serine-arginine rich splicing factor 1 (SRSF1) and SRSF6, on utilization of the 5'SS leading to lamin A or progerin production and a modulation of this regulation in the presence of the c.1824C\textgreaterT mutation is shown directly on HGPS patient cells. Mutant mice carrying the equivalent mutation in the LMNA gene (c.1827C\textgreaterT) also accumulate progerin and phenocopy the main cellular alterations and clinical defects of HGPS patients. RNAi-induced depletion of SRSF1 in the HGPS-like mouse embryonic fibroblasts (MEFs) allowed progerin reduction and dysmorphic nuclei phenotype correction, whereas SRSF6 depletion aggravated the HGPS-like MEF's phenotype. We demonstrate that changes in the splicing ratio between lamin A and progerin are key factors for lifespan since heterozygous mice harboring the mutation lived longer than homozygous littermates but less than the wild-type. Genetic and biochemical data together favor the view that physiological progerin production is under tight control of a conserved splicing mechanism to avoid precocious aging. |
| تدمد: | 1460-2083 0964-6906 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::07d814b0799cc4a5ebd703c809c3ce67Test https://doi.org/10.1093/hmg/ddr385Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....07d814b0799cc4a5ebd703c809c3ce67 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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