Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutation in the lamin A/C gene (LMNA); the mutant allele produces a truncated lamin A (“progerin”) that disrupts the nuclear architecture, interferes with cell cycle progression, and may accelerate cellular senescence.
HGPS is dominant, i.e., heterozygotes are fully affected, implying that the ratio of progerin to normal lamin is important. One would predict that more wildtype lamin would titrate out the mutant protein and lessen the severity of the disease. In a counterintuitive finding, Yang et al. demonstrate that the opposite is true: Mice that express only the lamin C isoform, but no lamin A, suffer from much milder progeria than mice expressing both isoforms:
Eliminating the synthesis of mature lamin a reduces disease phenotypes in mice carrying a hutchinson-gilford progeria syndrome allele
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 (LmnaHG) and found that heterozygous mice (LmnaHG/+) 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 LmnaHG allele and one LmnaLCO allele (a mutant allele that produces lamin C but no lamin A). We then compared the phenotypes of LmnaHG/LCO mice (which produce progerin and lamin C) with littermate LmnaHG/+ mice (which produce lamin A, lamin C, and progerin). LmnaHG/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, LmnaHG/LCO fibroblasts had fewer misshapen nuclei than LmnaHG/+ fibroblasts (P < 0.0001). A likely explanation for these differences was uncovered: the amount of progerin in LmnaHG/LCO fibroblasts and tissues was lower than in LmnaHG/+ 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.
Because the animals expressing only lamin C also have lower steady-state levels of progerin, it is possible that the net result is that wildtype lamin is titrating out the mutant protein after all. The mechanism of the progerin downregulation is unclear; the simplest model would seem to be that progerin is stabilized by lamin A but not lamin C.
Regardless, it’s still striking that a trait resulting from dominant mutation in a gene can be ameliorated by lowering levels of the wildtype protein. Does this imply that one could treat HGPS by targeting the wildtype allele of LMNA? Progerin arises at some low level during normal aging, and may contribute to cellular senescence; would lowering levels of lamin A slow the time-dependent accumulation of progerin in otherwise healthy humans?