期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 283, 期 11, 页码 7094-7099出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M708138200
关键词
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资金
- NHLBI NIH HHS [HL76839, HL86683] Funding Source: Medline
- NIAMS NIH HHS [AR050200] Funding Source: Medline
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 LmnaHG 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 body weight curves ( p< 0.0001), reduced numbers of spontaneous rib fractures ( p < 0.0001), and improved survival ( p < 0.0001). In addition, Lmna(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.
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