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J. Biol. Chem., Vol. 283, Issue 11, 7094-7099, March 14, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/11/7094    most recent M708138200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yang, S. H. Articles by Young, S. G. Search for Related Content PubMed PubMed Citation Articles by Yang, S. H. Articles by Young, S. G. Social Bookmarking                      What's this?

Eliminating the Synthesis of Mature Lamin A Reduces Disease Phenotypes in Mice Carrying a Hutchinson-Gilford Progeria Syndrome Allele^*

Shao H. Yang, Xin Qiao, Emily Farber, Sandy Y. Chang, Loren G. Fong¹, and Stephen G. Young²

From the Departments of Medicine and Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California 90095

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 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.

Received for publication, October 1, 2007 , and in revised form, December 14, 2007.

^* This work was supported in part by National Institutes of Health Grants AR050200, HL86683, and HL76839 and grants from the Progeria Research Foundation, The March of Dimes, and The Ellison Medical Research Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: 695 Charles E. Young Dr. South, Los Angeles, CA 90095. Tel.: 310-825-4422; Fax: 310-206-0865; E-mail: lfong{at}mednet.ucla.edu.

² Supported by a postdoctoral fellowship grant from the American Heart Association, Western States Affiliate. To whom correspondence may be addressed: 695 Charles E. Young Dr. South, Los Angeles, CA 90095. Tel.: 310-825-4422; Fax: 310-206-0865; E-mail: sgyoung{at}mednet.ucla.edu.

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