Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 118, Issue 10, Pages 3291-3300Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI35876
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Funding
- NIH [HL76839, CA099506, AR050200]
- Kentucky Lung Cancer Research Program [HL086683, GM66152]
- American Heart Association
- Vascular Biology Program at UCLA
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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 (Lmna(HG/+)). 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 (Lmna(nHG/+)). Lmna(nHG/+) mice developed the same disease phenotypes observed in Lmna(HG/+) 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 Lmna(nHG/+) 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.
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