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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.

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