Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome
Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome
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DOI：
10.1038/nm1204
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发表时间：
2005-04-01
期刊：
影响因子：
82.9
通讯作者：
Misteli, T
中科院分区：
文献类型：
--
作者：
Scaffidi, P;Misteli, T
Hutchinson-Gilford早衰综合征（HGPS）是由核纤层蛋白A（由LMNA编码）的自发点突变引起的儿童期过早衰老疾病，核纤层蛋白A是哺乳动物细胞核的主要结构元件之一（1-4）。HGPS突变激活LMNA前mRNA中的异常隐蔽剪接位点，导致截短核纤层蛋白A蛋白的合成和野生型核纤层蛋白A的伴随减少（3，4）。来自HGPS个体的成纤维细胞在核膜结构中具有严重的形态学异常。在这里，我们表明，细胞疾病表型是可逆的，在细胞从个人与HGPS。引入野生型核纤层蛋白A蛋白不能挽救细胞疾病症状。突变LMNA mRNA和核纤层蛋白A蛋白可以通过使用靶向活化的隐蔽剪接位点的修饰的寡核苷酸校正异常剪接事件来有效地消除。在剪接校正后，HGPS成纤维细胞呈现正常的核形态，异常的核分布和核纤层相关蛋白的细胞水平被挽救，异染色质特异性组蛋白修饰的缺陷被校正，并且重新建立了几个失调基因的正确表达。我们的研究结果为HGPS患者的过早衰老表型的纠正提供了原则依据。
Hutchinson-Gilford progeria syndrome (HGPS) is a childhood premature aging disease caused by a spontaneous point mutation in lamin A ( encoded by LMNA), one of the major architectural elements of the mammalian cell nucleus(1-4). The HGPS mutation activates an aberrant cryptic splice site in LMNA pre-mRNA, leading to synthesis of a truncated lamin A protein and concomitant reduction in wild-type lamin A(3,4). Fibroblasts from individuals with HGPS have severe morphological abnormalities in nuclear envelope structure. Here we show that the cellular disease phenotype is reversible in cells from individuals with HGPS. Introduction of wild-type lamin A protein does not rescue the cellular disease symptoms. The mutant LMNA mRNA and lamin A protein can be efficiently eliminated by correction of the aberrant splicing event using a modified oligonucleotide targeted to the activated cryptic splice site. Upon splicing correction, HGPS fibroblasts assume normal nuclear morphology, the aberrant nuclear distribution and cellular levels of lamina-associated proteins are rescued, defects in heterochromatin-specific histone modifications are corrected and proper expression of several misregulated genes is reestablished. Our results establish proof of principle for the correction of the premature aging phenotype in individuals with HGPS.