Journal article
Increasing the length of progerin’s isoprenyl anchor does not worsen bone disease or survival in mice with Hutchinson-Gilford progeria syndrome
Journal of lipid research, Vol.50(1), pp.126-134
01/2009
DOI: 10.1194/jlr.M800424-JLR200
PMCID: PMC3837462
PMID: 18757838
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is caused by the synthesis of a truncated prelamin A,
commonly called progerin, that contains a carboxyl-terminal farnesyl lipid anchor. The farnesyl
lipid anchor helps to target progerin to membrane surfaces at the nuclear rim, where it disrupts the
integrity of the nuclear lamina and causes misshapen nuclei. Several lines of evidence have
suggested that progerin’s farnesyl lipid anchor is crucial for the emergence of disease
phenotypes. Because a geranyl-geranyl lipid is ∼45-fold more potent than a farnesyl lipid in
anchoring proteins to lipid membranes, we hypothesized that a geranyl-geranylated version of
progerin might be more potent in eliciting disease phenotypes. To test this hypothesis, we used gene
targeting to create mice expressing geranyl-geranylated progerin
(
Lmna
ggHG/+
). We then compared
Lmna
ggHG/+
mice, side-by-side, with otherwise identical mice
expressing farnesylated progerin (
Lmna
HG/+
).
Geranyl-geranylation of progerin in
Lmna
ggHG/+
cells and
farnesylation of progerin in
Lmna
HG/+
cells was confirmed by
metabolic labeling. Contrary to our expectations,
Lmna
ggHG/+
mice survived longer than
Lmna
HG/+
mice. The
Lmna
ggHG/+
mice also exhibited milder bone disease. The
steady-state levels of progerin, relative to lamin C, were lower in
Lmna
ggHG/+
mice than in
Lmna
HG/+
mice, providing a potential explanation for the milder
disease in
Lmna
ggHG/+
mice.
Details
- Title: Subtitle
- Increasing the length of progerin’s isoprenyl anchor does not worsen bone disease or survival in mice with Hutchinson-Gilford progeria syndrome
- Creators
- Brandon S. J Davies - Department of Medicine, Human Genetics, University of California, Los Angeles, CA 90095Shao H Yang - Department of Medicine, Human Genetics, University of California, Los Angeles, CA 90095Emily Farber - Department of Medicine, Human Genetics, University of California, Los Angeles, CA 90095Roger Lee - Department of Medicine, Human Genetics, University of California, Los Angeles, CA 90095Suzanne B Buck - Molecular Probes-Invitrogen, Eugene OR 97402Douglas A Andres - Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536H. Peter Spielmann - Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536Brian J Agnew - Molecular Probes-Invitrogen, Eugene OR 97402Fuyuhiko Tamanoi - Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095Loren G Fong - Department of Medicine, Human Genetics, University of California, Los Angeles, CA 90095Stephen G Young - Department of Medicine, Human Genetics, University of California, Los Angeles, CA 90095
- Resource Type
- Journal article
- Publication Details
- Journal of lipid research, Vol.50(1), pp.126-134
- DOI
- 10.1194/jlr.M800424-JLR200
- PMID
- 18757838
- PMCID
- PMC3837462
- NLM abbreviation
- J Lipid Res
- ISSN
- 0022-2275
- eISSN
- 1539-7262
- Publisher
- American Society for Biochemistry and Molecular Biology
- Language
- English
- Date published
- 01/2009
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology
- Record Identifier
- 9984025288402771
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