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Progerin elicits disease phenotypes of progeria in mice whether or not it is farnesylated
Shao H. Yang, … , Stephen G. Young, Loren G. Fong
Shao H. Yang, … , Stephen G. Young, Loren G. Fong
Published September 2, 2008
Citation Information: J Clin Invest. 2008;118(10):3291-3300. https://doi.org/10.1172/JCI35876.
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Research Article Genetics

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

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Abstract

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.

Authors

Shao H. Yang, Douglas A. Andres, H. Peter Spielmann, Stephen G. Young, Loren G. Fong

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Figure 1

Production of mice that express a nonfarnesylated version of progerin.

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Production of mice that express a nonfarnesylated version of progerin.
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(A) The mutant allele yielding nonfarnesylated progerin, LmnanHG, was generated by deleting intron 10, intron 11, and the last 150 bp of exon 11 and introducing a point mutation in exon 12 that changes the cysteine of the CaaX motif to a serine. (B) Southern blot identification of the targeting event in 2 different mouse ES cell clones. The genomic DNA was cleaved with EcoRI, and the blot was hybridized with a 5′ flanking probe (location of probe shown in A). (C) Western blot identification of progerin in extracts of LmnanHG/+ MEFs with a lamin A/C–specific polyclonal antibody. Extracts of Lmna+/+, LmnaHG/+, and LmnaHG/HG MEFs were included as controls. (D) Sequencing chromatograms of PCR products amplified from the mutant alleles of LmnaHG/+ and LmnanHG/+ mice. The single nucleotide substitution in the LmnanHG allele (a thymine to adenine substitution) changes the cysteine of the CaaX motif to a serine.
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