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题目:: A conserved splicing mechanism of the LMNA gene controls premature aging.
作者:: Lopez-Mejia(Isabel C),Vautrot(Valentin),De Toledo(Marion),Behm-Ansmant(Isabelle),Bourgeois(Cyril F),Navarro(Claire L),Osorio(Fernando G),Freije(José M P),Stévenin(James),De Sandre-Giovannoli(Annachiara),Lopez-Otin(Carlos),Lévy(Nicolas),Branlant(Christiane),Tazi(Jamal)
状态:: 发布时间2011-11-08 , 更新时间 2015-11-19
期刊:: Hum Mol Genet
摘要:: 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.
语言:: eng
DOI:: 10.1093/hmg/ddr385

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