title: Eliminating the synthesis of mature lamin A reduces disease phenotypes in mice carrying a Hutchinson-Gilford progeria syndrome allele.
abstract: Hutchinson-Gilford progeria syndrome is caused by the synthesis of a mutant form of prelamin A, which is generally called progerin. Progerin is targeted to the nuclear rim, where it interferes with the integrity of the nuclear lamina, causes misshapen cell nuclei, and leads to multiple aging-like disease phenotypes. We created a gene-targeted allele yielding exclusively progerin (Lmna HG) and found that heterozygous mice (Lmna HG/+) exhibit many phenotypes of progeria. In this study, we tested the hypothesis that the phenotypes elicited by the Lmna HG allele might be modulated by compositional changes in the nuclear lamina. To explore this hypothesis, we bred mice harboring one Lmna HG allele and one Lmna LCO allele (a mutant allele that produces lamin C but no lamin A). We then compared the phenotypes of Lmna HG/LCO mice (which produce progerin and lamin C) with littermate Lmna HG/+ mice (which produce lamin A, lamin C, and progerin). Lmna HG/LCO mice exhibited improved HG/LCO fibroblasts had fewer misshapen nuclei than Lmna HG/+ fibroblasts (p < 0.0001). A likely explanation for these differences was uncovered; the amount of progerin in Lmna HG/LCO fibroblasts and tissues was lower than in Lmna HG/+ fibroblasts and tissues. These studies suggest that compositional changes in the nuclear lamina can influence both the steady-state levels of progerin and the severity of progeria-like disease phenotypes.
authors.affiliation: Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA.
authors.forename: Shao H
authors.initials: SH
authors.lastname: Yang
authors.forename: Xin
authors.initials: X
authors.lastname: Qiao
authors.forename: Emily
authors.initials: E
authors.lastname: Farber
authors.forename: Sandy Y
authors.initials: SY
authors.lastname: Chang
authors.forename: Loren G
authors.initials: LG
authors.lastname: Fong
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
mesh_terms: D000483:Alleles; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D050723:Fractures, Bone / Q000378:metabolism; D005786:Gene Expression Regulation; D034904:Lamin Type A / Q000096:biosynthesis* / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D011371:Progeria / Q000235:genetics*; D011498:Protein Precursors / Q000235:genetics
chemical_list: D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; C440308:lamin C; C090764:prelamin A