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Progerin elicits disease phenotypes of progeria in mice whether or not it is farnesylated.

http://www.ncbi.nlm.nih.gov/pubmed/18769635

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.

Pubmed ID: 18769635 RIS Download

Mesh terms: Animals | Blotting, Western | Body Weight | Bone and Bones | Cell Nucleus Shape | Disease Models, Animal | Female | Fibroblasts | Gene Expression Regulation | Liver | Male | Mice | Mice, Inbred C57BL | Mice, Transgenic | Nuclear Proteins | Phenotype | Point Mutation | Prenylation | Progeria | Protein Precursors | Survival Analysis

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Associated grants

  • Agency: NIAMS NIH HHS, Id: AR050200
  • Agency: NCI NIH HHS, Id: CA099506
  • Agency: NIGMS NIH HHS, Id: GM66152
  • Agency: NHLBI NIH HHS, Id: HL086683
  • Agency: NHLBI NIH HHS, Id: HL76839

Mouse Genome Informatics (Data, Gene Annotation)

OMIM (Data, Gene Annotation)

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