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

Shao H. Yang, Sandy Y. Chang, Shuxun Ren, Yibin Wang, Douglas A. Andres, H. Peter Spielmann, Loren G. Fong, Stephen G. Young

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58 Scopus citations


Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutant prelamin A, progerin, that terminates with a farnesylcysteine. HGPS knock-in mice (LmnaHG/+) 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 (LmnanHG/+ 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 LmnanHG/1 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 (LmnacsmHG) in which the carboxyl-terminal -CSIM motif was changed to -CSM. We then compared disease phenotypes in mice harboring the LmnanHG or LmnacsmHG allele. As expected, LmnanHG/+ and LmnanHG/nHG mice developed severe progeria-like disease phenotypes, including osteolytic lesions and rib fractures, osteoporosis, slow growth and reduced survival. In contrast, LmnacsmHG/+ and LmnacsmHG/csmHG mice exhibited no bone disease and displayed entirely normal body weights and survival. The frequencies of misshapen cell nuclei were lower in LmnacsmHG/+ and LmnacsmHG/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. Published by Oxford University Press 2010.

Original languageEnglish
Article numberddq490
Pages (from-to)436-444
Number of pages9
JournalHuman Molecular Genetics
Issue number3
StatePublished - Feb 2011

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health Grants (HL76839, CA099506-07, HL086683, HL089781); the Ellison Medical Foundation Senior Scholar Program; and a March of Dimes Grant (6-FY2007-1012); a Beginning Grant-in-aid from the American Heart Association, Western States Affiliate (0865262F) and a fellowship from the Vascular Biology Program at UCLA (2 T32 HL069766:06).

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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