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 progerialike disease phenotypes.Mutations in LMNA yield a host of different human diseases, including muscular dystrophy, partial lipodystrophy, and Hutchinson-Gilford progeria syndrome (HGPS) 3 (1-3). LMNA yields two principal proteins, prelamin A and lamin C (4). Prelamin A terminates with a CAAX motif (i.e. CSIM), which triggers farnesylation and methylation of a carboxyl-terminal cysteine (5, 6). Following these modifications, the carboxyl-terminal portion of prelamin A (including the farnesylcysteine methyl ester) is clipped off by ZMPSTE24 and degraded, releasing mature lamin A (6, 7). Lamin C does not contain a CAAX motif and is not farnesylated. Lamins A and C are important proteins of the nuclear lamina, a filamentous meshwork that lines the inner nuclear membrane (1-3). In the mouse, a complete absence of lamin A and lamin C leads to muscular dystrophy and death by 6 weeks of age (8). However, prelamin A and lamin A appear to be dispensable, as mice that are homozygous for a "lamin C-only" allele (Lmna LCO/LCO ) are healthy and robust (9).Hutchinson-Gilford progeria syndrome is a rare pediatric progeroid syndrome associated with the production of a mutant form of prelamin A (6, 10, 11). Patients with HGPS appear normal at birth but soon develop multiple disease phenotypes resembling premature aging (12). HGPS is almost always caused by a point mutation in LMNA that alters pre-mRNA splicing, resulting in a mutant form of prelamin A, commonly called progerin, with a 50-amino acid internal delet...