Abstract
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 nucleus1,2,3,4. 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 A3,4. 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.
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Acknowledgements
We thank J. Boers, T. Jenuwein, K. Wilson and G. Almouzni for reagents and K. Wilson, C. Stewart, B. Burke and J. Caceres for comments on the manuscript. T.M. is a Fellow of the Keith R. Porter Endowment for Cell Biology.
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Supplementary information
Supplementary Fig. 1
Correction of lamin A aberrant splicing in a minigene system. (PDF 90 kb)
Supplementary Fig. 2
Specificity of exo11 morpholino oligonucleotide. (PDF 163 kb)
Supplementary Fig. 3
Reversal of the cellular phenotype of HGPS fibroblasts does not require cell division and nuclear envelope disassembly. (PDF 657 kb)
Supplementary Table 1
Quantitation of cellular phenotypes. (PDF 26 kb)
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Scaffidi, P., Misteli, T. Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome. Nat Med 11, 440–445 (2005). https://doi.org/10.1038/nm1204
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DOI: https://doi.org/10.1038/nm1204
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