A conserved splicing mechanism of the LMNA gene controls premature aging
A conserved splicing mechanism of the LMNA gene controls premature aging
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DOI：
10.1093/hmg/ddr385
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发表时间：
2011-12-01
影响因子：
3.5
通讯作者：
Tazi, Jamal
中科院分区：
文献类型：
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作者：
Lopez-Mejia, Isabel C.;Vautrot, Valentin;Tazi, Jamal
哈钦森-吉尔福德早衰综合征（HGPS）是一种罕见的遗传疾病，其表型特征是早衰的许多特征。大多数HGPS病例是由于杂合沉默突变（c.1824C > T; p.Gly608Gly），该突变增强了LMNA前mrna外显子11的内部5‘剪接位点（5’ ss）的使用，并导致产生具有显性负作用的截断蛋白（progerin）。在这里，我们发现HGPS突变改变了LMNA外显子11的5'SS的可及性，该外显子被隔离在保守的RNA结构中。我们的研究结果还揭示了一组富含丝氨酸精氨酸（SR）的蛋白质，包括富含丝氨酸精氨酸的剪接因子1 （SRSF1）和SRSF6，对利用5ss导致层粘连蛋白a或早孕蛋白产生的调节作用，并且在HGPS患者细胞中直接显示了c.1824C > T突变存在时这种调节的调节作用。携带LMNA基因（c.1827C > T）等效突变的突变小鼠也积累了progerin，并表现出HGPS患者的主要细胞改变和临床缺陷。rnai诱导的hgps样小鼠胚胎成纤维细胞（MEF）中SRSF1的缺失导致了早孕蛋白的减少和畸形核的表型纠正，而SRSF6的缺失则加重了hgps样MEF的表型。我们证明，层合蛋白A和progerin之间剪接比率的变化是影响寿命的关键因素，因为携带突变的杂合小鼠比纯合小鼠寿命更长，但比野生型小鼠寿命短。遗传和生化数据共同支持这样一种观点，即生理上的早衰蛋白的产生受到保守剪接机制的严格控制，以避免早衰。
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.