A conserved splicing mechanism of the LMNA gene controls premature aging

• DOI: 10.1093/hmg/ddr385
• Publication Date: 2011-08-30T00:27:07Z
• Authors: Isabel C. Lopez-M...; Valentin Vautrot; Marion De Toledo; Isabelle Behm-Ans...; Cyril F. Bourgeois; Claire L. Navarro; Fernando G. Osorio; José M. P. Freije; James Stévenin; Annachiara De San...; Carlos Lopez-Otin; Nicolas Lévy; Christiane Branlant; Jamal Tazi
• Keywords: LMNA; Progeria; Premature aging; Phenocopy; Splicing factor

Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder phenotypically characterized by many features of premature aging. Most cases HGPS are due to heterozygous silent mutation (c.1824C>T; p.Gly608Gly) that enhances the use an internal 5′ splice site (5′SS) in exon 11 LMNA pre-mRNA and leads production truncated protein (progerin) with dominant negative effect. Here we show changes accessibility 5′SS which sequestered conserved RNA structure. Our results also reveal regulatory role subset serine–arginine (SR)-rich proteins, including rich splicing factor 1 (SRSF1) SRSF6, on utilization leading lamin A or progerin modulation this regulation presence c.1824C>T shown directly patient cells. Mutant mice carrying equivalent gene (c.1827C>T) accumulate phenocopy main cellular alterations clinical defects patients. RNAi-induced depletion SRSF1 HGPS-like mouse embryonic fibroblasts (MEFs) allowed reduction dysmorphic nuclei phenotype correction, whereas SRSF6 aggravated MEF's phenotype. We demonstrate ratio between key factors for lifespan since harboring lived longer than homozygous littermates but less wild-type. Genetic biochemical data together favor view physiological under tight control mechanism avoid precocious