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Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome

Nature Medicine volume 11, pages 440–445 (2005)Cite this article

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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Figure 1: Wild-type lamin A is insufficient for phenotypic rescue of HGPS cells.
Figure 2: Correction of aberrant splicing in the endogenous lamin A transcript in HGPS cells.
Figure 3: Phenotypic rescue of HGPS cells by treatment with morpholino oligonucleotide.
Figure 4: Restoration of normal gene activity in HGPS cells by treatment with oligonucleotide.

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References

  1. DeBusk, F.L. The Hutchinson-Gilford progeria syndrome. Report of 4 cases and review of the literature. J. Pediatr. 80, 697–724 (1972).

    Article  CAS  Google Scholar 

  2. Uitto, J. Searching for clues to premature aging. Trends Endocrinol. Metab. 13, 140–141 (2002).

    Article  CAS  Google Scholar 

  3. Eriksson, M. et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423, 293–298 (2003).

    Article  CAS  Google Scholar 

  4. De Sandre-Giovannoli, A. et al. Lamin A truncation in Hutchinson-Gilford progeria. Science 300, 2055 (2003).

    Article  CAS  Google Scholar 

  5. Csoka, A.B. et al. Novel lamin A/C gene (LMNA) mutations in atypical progeroid syndromes. J. Med. Genet. 41, 304–308 (2004).

    Article  CAS  Google Scholar 

  6. Goldman, R.D. et al. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc. Natl. Acad. Sci. USA 101, 8963–8968 (2004).

    Article  CAS  Google Scholar 

  7. Ye, Q., Callebaut, I., Pezhman, A., Courvalin, J.C. & Worman, H.J. Domain-specific interactions of human HP1-type chromodomain proteins and inner nuclear membrane protein LBR. J. Biol. Chem. 272, 14983–14989 (1997).

    Article  CAS  Google Scholar 

  8. Jenuwein, T. & Allis, C.D. Translating the histone code. Science 293, 1074–1080 (2001).

    Article  CAS  Google Scholar 

  9. Holt, I. et al. Effect of pathogenic mis-sense mutations in lamin A on its interaction with emerin in vivo. J. Cell Sci. 116, 3027–3035 (2003).

    Article  CAS  Google Scholar 

  10. Vaughan, A. et al. Both emerin and lamin C depend on lamin A for localization at the nuclear envelope. J. Cell Sci. 114, 2577–2590 (2001).

    CAS  Google Scholar 

  11. Johnson, B.R. et al. A-type lamins regulate retinoblastoma protein function by promoting subnuclear localization and preventing proteasomal degradation. Proc. Natl. Acad. Sci. USA 101, 9677–9682 (2004).

    Article  CAS  Google Scholar 

  12. Sazani, P. & Kole, R. Therapeutic potential of antisense oligonucleotides as modulators of alternative splicing. J. Clin. Invest. 112, 481–486 (2003).

    Article  CAS  Google Scholar 

  13. Giles, R.V., Spiller, D.G., Clark, R.E. & Tidd, D.M. Antisense morpholino oligonucleotide analog induces missplicing of C-myc mRNA. Antisense Nucleic Acid Drug Dev. 9, 213–220 (1999).

    Article  CAS  Google Scholar 

  14. Summerton, J. Morpholino antisense oligomers: the case for an RNase H-independent structural type. Biochim. Biophys. Acta 1489, 141–158 (1999).

    Article  CAS  Google Scholar 

  15. Lin, F. & Worman, H.J. Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C. J. Biol. Chem. 268, 16321–16326 (1993).

    CAS  Google Scholar 

  16. Summerton, J. et al. Morpholino and phosphorothioate antisense oligomers compared in cell-free and in-cell systems. Antisense Nucleic Acid Drug Dev. 7, 63–70 (1997).

    Article  CAS  Google Scholar 

  17. Ly, D.H., Lockhart, D.J., Lerner, R.A. & Schultz, P.G. Mitotic misregulation and human aging. Science 287, 2486–2492 (2000).

    Article  CAS  Google Scholar 

  18. Csoka, A.B. et al. Genome-scale expression profiling of Hutchinson-Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/mesenchymal defects and accelerated atherosclerosis. Aging Cell 3, 235–243 (2004).

    Article  CAS  Google Scholar 

  19. Mounkes, L.C., Kozlov, S., Hernandez, L., Sullivan, T. & Stewart, C.L. A progeroid syndrome in mice is caused by defects in A-type lamins. Nature 423, 298–301 (2003).

    Article  CAS  Google Scholar 

  20. Moulton, H.M., Nelson, M.H., Hatlevig, S.A., Reddy, M.T. & Iversen, P.L. Cellular uptake of antisense morpholino oligomers conjugated to arginine-rich peptides. Bioconjug. Chem. 15, 290–299 (2004).

    Article  CAS  Google Scholar 

  21. Gebski, B.L., Mann, C.J., Fletcher, S. & Wilton, S.D. Morpholino antisense oligonucleotide induced dystrophin exon 23 skipping in mdx mouse muscle. Hum. Mol. Genet. 12, 1801–1811 (2003).

    Article  CAS  Google Scholar 

  22. Garcia-Blanco, M.A., Baraniak, A.P. & Lasda, E.L. Alternative splicing in disease and therapy. Nat. Biotechnol. 22, 535–546 (2004).

    Article  CAS  Google Scholar 

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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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Authors and Affiliations

  1. National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, 20892, Maryland, USA

    Paola Scaffidi & Tom Misteli

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  1. Paola Scaffidi
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Correspondence to Tom Misteli.

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The authors declare no competing financial interests.

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)

Supplementary Methods (PDF 58 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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