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Absence of progeria-like disease phenotypes in knock-in mice expressing a non-farnesylated version of progerin.

Publication ,  Journal Article
Yang, SH; Chang, SY; Ren, S; Wang, Y; Andres, DA; Spielmann, HP; Fong, LG; Young, SG
Published in: Hum Mol Genet
February 1, 2011

Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutant prelamin A, progerin, that terminates with a farnesylcysteine. HGPS knock-in mice (Lmna(HG/+)) develop severe progeria-like disease phenotypes. These phenotypes can be ameliorated with a protein farnesyltransferase inhibitor (FTI), suggesting that progerin's farnesyl lipid is important for disease pathogenesis and raising the possibility that FTIs could be useful for treating humans with HGPS. Subsequent studies showed that mice expressing non-farnesylated progerin (Lmna(nHG/+) mice, in which progerin's carboxyl-terminal -CSIM motif was changed to -SSIM) also develop severe progeria, raising doubts about whether any treatment targeting protein prenylation would be particularly effective. We suspected that those doubts might be premature and hypothesized that the persistent disease in Lmna(nHG/+) mice could be an unanticipated consequence of the cysteine-to-serine substitution that was used to eliminate farnesylation. To test this hypothesis, we generated a second knock-in allele yielding non-farnesylated progerin (Lmna(csmHG)) in which the carboxyl-terminal -CSIM motif was changed to -CSM. We then compared disease phenotypes in mice harboring the Lmna(nHG) or Lmna(csmHG) allele. As expected, Lmna(nHG/+) and Lmna(nHG/nHG) mice developed severe progeria-like disease phenotypes, including osteolytic lesions and rib fractures, osteoporosis, slow growth and reduced survival. In contrast, Lmna(csmHG/+) and Lmna(csmHG/csmHG) mice exhibited no bone disease and displayed entirely normal body weights and survival. The frequencies of misshapen cell nuclei were lower in Lmna(csmHG/+) and Lmna(csmHG/csmHG) fibroblasts. These studies show that the ability of non-farnesylated progerin to elicit disease depends on the carboxyl-terminal mutation used to eliminate protein prenylation.

Duke Scholars

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

February 1, 2011

Volume

20

Issue

3

Start / End Page

436 / 444

Location

England

Related Subject Headings

  • Protein Prenylation
  • Protein Precursors
  • Progeria
  • Phenotype
  • Nuclear Proteins
  • Mutation
  • Mice
  • Male
  • Lamin Type A
  • Imidazoles
 

Citation

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Yang, S. H., Chang, S. Y., Ren, S., Wang, Y., Andres, D. A., Spielmann, H. P., … Young, S. G. (2011). Absence of progeria-like disease phenotypes in knock-in mice expressing a non-farnesylated version of progerin. Hum Mol Genet, 20(3), 436–444. https://doi.org/10.1093/hmg/ddq490
Yang, Shao H., Sandy Y. Chang, Shuxun Ren, Yibin Wang, Douglas A. Andres, H Peter Spielmann, Loren G. Fong, and Stephen G. Young. “Absence of progeria-like disease phenotypes in knock-in mice expressing a non-farnesylated version of progerin.Hum Mol Genet 20, no. 3 (February 1, 2011): 436–44. https://doi.org/10.1093/hmg/ddq490.
Yang SH, Chang SY, Ren S, Wang Y, Andres DA, Spielmann HP, et al. Absence of progeria-like disease phenotypes in knock-in mice expressing a non-farnesylated version of progerin. Hum Mol Genet. 2011 Feb 1;20(3):436–44.
Yang, Shao H., et al. “Absence of progeria-like disease phenotypes in knock-in mice expressing a non-farnesylated version of progerin.Hum Mol Genet, vol. 20, no. 3, Feb. 2011, pp. 436–44. Pubmed, doi:10.1093/hmg/ddq490.
Yang SH, Chang SY, Ren S, Wang Y, Andres DA, Spielmann HP, Fong LG, Young SG. Absence of progeria-like disease phenotypes in knock-in mice expressing a non-farnesylated version of progerin. Hum Mol Genet. 2011 Feb 1;20(3):436–444.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

February 1, 2011

Volume

20

Issue

3

Start / End Page

436 / 444

Location

England

Related Subject Headings

  • Protein Prenylation
  • Protein Precursors
  • Progeria
  • Phenotype
  • Nuclear Proteins
  • Mutation
  • Mice
  • Male
  • Lamin Type A
  • Imidazoles