title: Enhanced SRSF5 Protein Expression Reinforces Lamin A mRNA Production in HeLa Cells and Fibroblasts of Progeria Patients.
abstract: The Hutchinson Gilford Progeria Syndrome (HGPS) is a rare genetic disease leading to accelerated aging. Three mutations of the LMNA gene leading to HGPS were identified. The more frequent ones, c.1824C>T and c.1822G>A, enhance the use of the intron 11 progerin 5'splice site (5'SS) instead of the LMNA 5'SS, leading to the production of the truncated dominant negative progerin. The less frequent c.1868C>G mutation creates a novel 5'SS (LAΔ35 5'SS), inducing the production of another truncated LMNA protein (LAΔ35). Our data show that the progerin 5'SS is used at low yield in the absence of HGPS mutation, whereas utilization of the LAΔ35 5'SS is dependent upon the presence of the c.1868C>G mutation. In the perspective to correct HGPS splicing defects, we investigated whether SR proteins can modify the relative yields of utilization of intron 11 5'SSs. By in cellulo and in vitro assays, we identified SRSF5 as a direct key regulator increasing the utilization of the LMNA 5'SS in the presence of the HGPS mutations. Enhanced SRSF5 expression in dermal fibroblasts of HGPS patients as well as PDGF-BB stimulation of these cells decreased the utilization of the progerin 5'SS, and improves nuclear morphology, opening new therapeutic perspectives for premature aging.
authors.affiliation: IMoPA (Ingénierie Moléculaire et Physiopathologie Articulaire), UMR 7365 CNRS-UL, Biopôle de l'Université de Lorraine, Vandoeuvre-lès-Nancy, 54505, France.
authors.forename: Valentin
authors.initials: V
authors.lastname: Vautrot
authors.affiliation: IMoPA (Ingénierie Moléculaire et Physiopathologie Articulaire), UMR 7365 CNRS-UL, Biopôle de l'Université de Lorraine, Vandoeuvre-lès-Nancy, 54505, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Aigueperse
authors.affiliation: IMoPA (Ingénierie Moléculaire et Physiopathologie Articulaire), UMR 7365 CNRS-UL, Biopôle de l'Université de Lorraine, Vandoeuvre-lès-Nancy, 54505, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Oillo-Blanloeil
authors.affiliation: FR3209 CNRS, Biopôle de l'Université de Lorraine, Vandoeuvre-lès-Nancy, 54505, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Hupont
authors.affiliation: IGBMC Department of Functional Genomics and Cancer, CNRS UMR 7104, INSERM U 964, University of Strasbourg, Illkirch Cedex, 67404, France.
authors.forename: James
authors.initials: J
authors.lastname: Stevenin
authors.affiliation: IMoPA (Ingénierie Moléculaire et Physiopathologie Articulaire), UMR 7365 CNRS-UL, Biopôle de l'Université de Lorraine, Vandoeuvre-lès-Nancy, 54505, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Branlant
authors.affiliation: IMoPA (Ingénierie Moléculaire et Physiopathologie Articulaire), UMR 7365 CNRS-UL, Biopôle de l'Université de Lorraine, Vandoeuvre-lès-Nancy, 54505, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Behm-Ansmant
mesh_terms: D005347:Fibroblasts / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D011371:Progeria / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D034904:Lamin Type A; D012333:RNA, Messenger; D016601:RNA-Binding Proteins
keywords: Hutchinson Gilford Progeria Syndrome; LMNA; PDGF-BB; SRSF1; SRSF5; alternative splicing