title: Increasing the length of progerin's isoprenyl anchor does not worsen bone disease or survival in mice with Hutchinson-Gilford progeria syndrome.
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 geranylgeranyl lipid is approximately 45-fold more potent than a farnesyl lipid in anchoring proteins to lipid membranes, we hypothesized that a geranylgeranylated version of progerin might be more potent in eliciting disease phenotypes. To test this hypothesis, we used gene targeting to create mice expressing geranylgeranylated progerin (Lmna(ggHG/+)). We then compared Lmna(ggHG/+) mice, side-by-side, with otherwise identical mice expressing farnesylated progerin (Lmna(HG/+)). Geranylgeranylation 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.
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Brandon S J
authors.initials: BS
authors.lastname: Davies
authors.forename: Shao H
authors.initials: SH
authors.lastname: Yang
authors.forename: Emily
authors.initials: E
authors.lastname: Farber
authors.forename: Roger
authors.initials: R
authors.lastname: Lee
authors.forename: Suzanne B
authors.initials: SB
authors.lastname: Buck
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Andres
authors.forename: H Peter
authors.initials: HP
authors.lastname: Spielmann
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Agnew
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Tamanoi
authors.forename: Loren G
authors.initials: LG
authors.lastname: Fong
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young