Human Molecular Genetics Advance Access published online on August 26, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi326
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Human Genetics, University of Michigan, Ann Arbor, MI
* To whom correspondence should be addressed. Hutchinson-Gilford progeria syndrome (HGPS) is typically caused by mutations in codon 608 (G608G) of the LMNA gene, which activates a cryptic splice site resulting in the in-frame loss of 150 nucleotides from the lamin A message. The deleted region includes a protein cleavage site that normally removes 15 amino acids, including a CAAX box farnesylation site, from the lamin A protein. We investigated the processing of the C-terminus of the mutant protein, ‘progerin’, and found that it does not undergo cleavage and, indeed, remains farnesylated. The retention of the farnesyl group may have numerous consequences, as farnesyl groups increase lipophilicity and are involved in membrane association and in protein interactions, and is likely to be an important factor in the HGPS phenotype. To further investigate this, we studied the effects of farnesylation inhibition on nuclear phenotypes in cells expressing normal and mutant lamin A. Expression of a GFP-progerin fusion protein in normal fibroblasts caused a high incidence of nuclear abnormalities, as was also seen in HGPS fibroblasts, and resulted in abnormal nuclear localization of GFP-progerin in comparison to the localization pattern of GFP-lamin A. Expression of a GFP-lamin A fusion containing a mutation preventing the final cleavage step, causing the protein to remain farnesylated, displayed identical localization patterns and nuclear abnormalities as in HGPS cells and in cells expressing GFP-progerin. Exposure to a farnesyltransferase inhibitor (FTI), PD169541, caused a significant improvement in the nuclear morphology of cells expressing GFP-progerin and in HGPS cells. These results implicate the abnormal farnesylation of progerin in the cellular phenotype in HGPS cells and suggest that FTIs may represent a therapeutic option for patients with HGPS.
Received May 5, 2005
Revised August 23, 2005
Accepted August 23, 2005
Article
Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition
2 Department of Human Genetics, University of Michigan, 4909 Buhl, Box 0618, 1241 E. Catherine Street, Ann Arbor, MI 48109-0618
Thomas W. Glover, E-mail: glover{at}umich.edu
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. G. Fong, T. A. Vickers, E. A. Farber, C. Choi, U. J. Yun, Y. Hu, S. H. Yang, C. Coffinier, R. Lee, L. Yin, et al. Activating the synthesis of progerin, the mutant prelamin A in Hutchinson-Gilford progeria syndrome, with antisense oligonucleotides Hum. Mol. Genet., July 1, 2009; 18(13): 2462 - 2471. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Webster, K. L. Witkin, and O. Cohen-Fix Sizing up the nucleus: nuclear shape, size and nuclear-envelope assembly J. Cell Sci., May 15, 2009; 122(10): 1477 - 1486. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. N. Malhas, C. F. Lee, and D. J. Vaux Lamin B1 controls oxidative stress responses via Oct-1 J. Cell Biol., January 12, 2009; 184(1): 45 - 55. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. K. Agarwal, I. Kazachkova, S. Ten, and A. Garg Severe Mandibuloacral Dysplasia-Associated Lipodystrophy and Progeria in a Young Girl with a Novel Homozygous Arg527Cys LMNA Mutation J. Clin. Endocrinol. Metab., December 1, 2008; 93(12): 4617 - 4623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H Sagelius, Y Rosengardten, E Schmidt, C Sonnabend, B Rozell, and M Eriksson Reversible phenotype in a mouse model of Hutchinson-Gilford progeria syndrome J. Med. Genet., December 1, 2008; 45(12): 794 - 801. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. A. Kudlow, M. N. Stanfel, C. R. Burtner, E. D. Johnston, and B. K. Kennedy Suppression of Proliferative Defects Associated with Processing-defective Lamin A Mutants by hTERT or Inactivation of p53 Mol. Biol. Cell, December 1, 2008; 19(12): 5238 - 5248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Barrowman, C. Hamblet, C. M. George, and S. Michaelis Analysis of Prelamin A Biogenesis Reveals the Nucleus to be a CaaX Processing Compartment Mol. Biol. Cell, December 1, 2008; 19(12): 5398 - 5408. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. C. Capell, M. Olive, M. R. Erdos, K. Cao, D. A. Faddah, U. L. Tavarez, K. N. Conneely, X. Qu, H. San, S. K. Ganesh, et al. A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model PNAS, October 14, 2008; 105(41): 15902 - 15907. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Liu, T. H. McCalmont, I. J. Frieden, M. L. Williams, M. K. Connolly, and A. E. Gilliam The Stiff Skin Syndrome: Case Series, Differential Diagnosis of the Stiff Skin Phenotype, and Review of the Literature Arch Dermatol, October 1, 2008; 144(10): 1351 - 1359. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. R. Warner Research on Hutchinson-Gilford Progeria Syndrome J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2008; 63(8): 775 - 776. [Full Text] [PDF]
|
|
|
|
|
|
L. B. Gordon, C. J. Harling-Berg, and F. G. Rothman Highlights of the 2007 Progeria Research Foundation Scientific Workshop: Progress in Translational Science J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2008; 63(8): 777 - 787. [Full Text] [PDF]
|
|
|
|
|
|
Y. Wang, A. A. Panteleyev, D. M. Owens, K. Djabali, C. L. Stewart, and H. J. Worman Epidermal expression of the truncated prelamin A causing Hutchinson-Gilford progeria syndrome: effects on keratinocytes, hair and skin Hum. Mol. Genet., August 1, 2008; 17(15): 2357 - 2369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Coffinier, S. E. Hudon, R. Lee, E. A. Farber, C. Nobumori, J. H. Miner, D. A. Andres, H. P. Spielmann, C. A. Hrycyna, L. G. Fong, et al. A Potent HIV Protease Inhibitor, Darunavir, Does Not Inhibit ZMPSTE24 or Lead to an Accumulation of Farnesyl-prelamin A in Cells J. Biol. Chem., April 11, 2008; 283(15): 9797 - 9804. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Dechat, K. Pfleghaar, K. Sengupta, T. Shimi, D. K. Shumaker, L. Solimando, and R. D. Goldman Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin Genes & Dev., April 1, 2008; 22(7): 832 - 853. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Yang, X. Qiao, E. Farber, S. Y. Chang, L. G. Fong, and S. G. Young Eliminating the Synthesis of Mature Lamin A Reduces Disease Phenotypes in Mice Carrying a Hutchinson-Gilford Progeria Syndrome Allele J. Biol. Chem., March 14, 2008; 283(11): 7094 - 7099. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Merideth, L. B. Gordon, S. Clauss, V. Sachdev, A. C.M. Smith, M. B. Perry, C. C. Brewer, C. Zalewski, H. J. Kim, B. Solomon, et al. Phenotype and Course of Hutchinson-Gilford Progeria Syndrome N. Engl. J. Med., February 7, 2008; 358(6): 592 - 604. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Liu, Y. Wang, A. E. Rusinol, M. S. Sinensky, J. Liu, S. M. Shell, and Y. Zou Involvement of xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A FASEB J, February 1, 2008; 22(2): 603 - 611. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. B. Gordon, K. M. McCarten, A. Giobbie-Hurder, J. T. Machan, S. E. Campbell, S. D. Berns, and M. W. Kieran Disease Progression in Hutchinson-Gilford Progeria Syndrome: Impact on Growth and Development Pediatrics, October 1, 2007; 120(4): 824 - 833. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Afilalo, I. A. Sebag, L. E. Chalifour, D. Rivas, R. Akter, K. Sharma, and G. Duque Age-related changes in lamin A/C expression in cardiomyocytes Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1451 - H1456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. C. Capell, F. S. Collins, and E. G. Nabel Mechanisms of Cardiovascular Disease in Accelerated Aging Syndromes Circ. Res., July 6, 2007; 101(1): 13 - 26. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Malhas, C. F. Lee, R. Sanders, N. J. Saunders, and D. J. Vaux Defects in lamin B1 expression or processing affect interphase chromosome position and gene expression J. Cell Biol., February 26, 2007; 176(5): 593 - 603. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Young, M. Meta, S. H. Yang, and L. G. Fong Prelamin A Farnesylation and Progeroid Syndromes J. Biol. Chem., December 29, 2006; 281(52): 39741 - 39745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Liu, A. Rusinol, M. Sinensky, Y. Wang, and Y. Zou DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A J. Cell Sci., November 15, 2006; 119(22): 4644 - 4649. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Navarro, P. Cau, and N. Levy Molecular bases of progeroid syndromes Hum. Mol. Genet., October 15, 2006; 15(suppl_2): R151 - R161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Rusinol and M. S. Sinensky Farnesylated lamins, progeroid syndromes and farnesyl transferase inhibitors. J. Cell Sci., August 15, 2006; 119(Pt 16): 3265 - 3272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. L.R.M. Verstraeten, J. L.V. Broers, M. A.M. van Steensel, S. Zinn-Justin, F. C.S. Ramaekers, P. M. Steijlen, M. Kamps, H. J.H. Kuijpers, D. Merckx, H. J.M. Smeets, et al. Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation Hum. Mol. Genet., August 15, 2006; 15(16): 2509 - 2522. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. N. Dahl, P. Scaffidi, M. F. Islam, A. G. Yodh, K. L. Wilson, and T. Misteli Distinct structural and mechanical properties of the nuclear lamina in Hutchinson-Gilford progeria syndrome PNAS, July 5, 2006; 103(27): 10271 - 10276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Delbarre, M. Tramier, M. Coppey-Moisan, C. Gaillard, J.-C. Courvalin, and B. Buendia The truncated prelamin A in Hutchinson-Gilford progeria syndrome alters segregation of A-type and B-type lamin homopolymers Hum. Mol. Genet., April 1, 2006; 15(7): 1113 - 1122. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. G. Fong, D. Frost, M. Meta, X. Qiao, S. H. Yang, C. Coffinier, and S. G. Young A Protein Farnesyltransferase Inhibitor Ameliorates Disease in a Mouse Model of Progeria Science, March 17, 2006; 311(5767): 1621 - 1623. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Varga, M. Eriksson, M. R. Erdos, M. Olive, I. Harten, F. Kolodgie, B. C. Capell, J. Cheng, D. Faddah, S. Perkins, et al. Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson-Gilford progeria syndrome PNAS, February 28, 2006; 103(9): 3250 - 3255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. McClintock, L. B. Gordon, and K. Djabali Hutchinson-Gilford progeria mutant lamin A primarily targets human vascular cells as detected by an anti-Lamin A G608G antibody PNAS, February 14, 2006; 103(7): 2154 - 2159. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. Young, L. G. Fong, and S. Michaelis Thematic Review Series: Lipid Posttranslational Modifications. Prelamin A, Zmpste24, misshapen cell nuclei, and progeria--new evidence suggesting that protein farnesylation could be important for disease pathogenesis J. Lipid Res., December 1, 2005; 46(12): 2531 - 2558. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Davenport Turning Back the Clock Sci. Aging Knowl. Environ., October 5, 2005; 2005(40): nf78 - nf78. [Abstract] [Full Text]
|
|