title: A conserved splicing mechanism of the LMNA gene controls premature aging.
abstract: 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>T; 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>T mutation is shown directly on HGPS patient cells. Mutant mice carrying the equivalent mutation in the LMNA gene (c.1827C>T) 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.
authors.affiliation: CNRS, UMR 5535, University of Montpellier, Institut de Génétique Moléculaire de Montpellier, 1919 Route de Mende, Montpellier 34293, France.
authors.forename: Isabel C
authors.initials: IC
authors.lastname: Lopez-Mejia
authors.forename: Valentin
authors.initials: V
authors.lastname: Vautrot
authors.forename: Marion
authors.initials: M
authors.lastname: De Toledo
authors.forename: Isabelle
authors.initials: I
authors.lastname: Behm-Ansmant
authors.forename: Cyril F
authors.initials: CF
authors.lastname: Bourgeois
authors.forename: Claire L
authors.initials: CL
authors.lastname: Navarro
authors.forename: Fernando G
authors.initials: FG
authors.lastname: Osorio
authors.forename: José M P
authors.initials: JM
authors.lastname: Freije
authors.forename: James
authors.initials: J
authors.lastname: Stévenin
authors.forename: Annachiara
authors.initials: A
authors.lastname: De Sandre-Giovannoli
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopez-Otin
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lévy
authors.forename: Christiane
authors.initials: C
authors.lastname: Branlant
authors.forename: Jamal
authors.initials: J
authors.lastname: Tazi
mesh_terms: D019588:Aging, Premature / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017124:Conserved Sequence / Q000235:genetics; D019143:Evolution, Molecular; D005091:Exons / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009690:Nucleic Acid Conformation; D011371:Progeria / Q000235:genetics / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics; D012313:RNA / Q000737:chemistry / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D014162:Transfection
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011498:Protein Precursors; D022821:RNA Splice Sites; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C090764:prelamin A; D000068103:Serine-Arginine Splicing Factors; D012313:RNA