Hutchinson-Gilford progeria syndrome (HGPS), a rare disease that results in what 
appears to be premature aging, is caused by the production of a mutant form of 
prelamin A known as progerin. Progerin retains a farnesyl lipid anchor at its 
carboxyl terminus, a modification that is thought to be important in disease 
pathogenesis. Inhibition of protein farnesylation improves the hallmark nuclear 
shape abnormalities in HGPS cells and ameliorates disease phenotypes in mice 
harboring a knockin HGPS mutation (LmnaHG/+). The amelioration of disease, 
however, is incomplete, leading us to hypothesize that nonfarnesylated progerin 
also might be capable of eliciting disease. To test this hypothesis, we created 
knockin mice expressing nonfarnesylated progerin (LmnanHG/+). LmnanHG/+ mice 
developed the same disease phenotypes observed in LmnaHG/+ mice, although the 
phenotypes were milder, and mouse embryonic fibroblasts (MEFs) derived from 
these mice contained fewer misshapen nuclei. The steady-state levels of progerin 
in LmnanHG/+ MEFs and tissues were lower, suggesting a possible explanation for 
the milder phenotypes. These data support the concept that inhibition of protein 
farnesylation in progeria could be therapeutically useful but also suggest that 
this approach may be limited, as progerin elicits disease phenotypes whether or 
not it is farnesylated.