Figure 2.

The effects of disrupting A-type lamin synthesis and processing in laboratory mice. (A) Wild-type mice produce both lamin C and prelamin A. Prelamin A then undergoes four sequential posttranslational processing steps to generate mature lamin A. (B) Lmna^−/− mice produce neither lamin A nor lamin C. These mice have muscular dystrophy and die at 5–6 weeks of age.⁵ (C) Lmna^LCO/LCO mice produce only lamin C. These mice appear to be phenotypically normal.⁴² (D) Lmna^PLAO/PLAO mice do not produce lamin C. The prelamin A produced by these mice is efficiently converted to mature lamin A. These mice also appear to be normal.³³ (E) Lmna^LAO/LAO mice produce mature lamin A directly, bypassing prelamin A synthesis and processing. These mice make no lamin C. Like Lmna^LCO/LCO and Lmna^PLAO/PLAO mice, Lmna^LAO/LAO mice appear to be normal.⁴⁸ (F) Lmna^nPLAO/nPLAO produce exclusively nonfarnesylated prelamin A. Because of a cysteine-to-serine substitution in prelamin A's CaaX motif, the prelamin A cannot be farnesylated. These mice develop dilated cardiomyopathy and have reduced survival.³³ (G) Zmpste24-deficient mice produce both lamin C and prelamin A, but the final endoproteolytic step does not occur, resulting in the accumulation of farnesylated prelamin A. These mice display multiple progeria-like disease phenotypes.¹⁶,¹⁹ (H) In addition to making normal lamin C and prelamin A from one allele, Lmna^HG/+ mice make a prelamin A with a 50-amino acid internal deletion (from the Lmna^HG allele). This deletion prevents the final, ZMPSTE24-mediated, endoproteolytic step from occurring and leads to the accumulation of a farnesylated and truncated form of prelamin A called progerin. Despite the presence of normal forms of lamin A and lamin C, these mice develop progeria-like disease phenotypes.²⁸,²⁹ (I) Lmna^nHG/+ mice are identical to LmnaHG/+ mice except that the truncated prelamin A generated from the Lmna^nHG allele cannot be farnesylated (due to a cysteine-to-serine substitution in the CaaX motif), leading to the accumulation of nonfarnesylated progerin. These mice also have progeria, though it is somewhat less severe than that found in Lmna^HG/+ mice.²²