Lamin A and
lamin C, both products of Lmna, are key components of the nuclear lamina. In the mouse, a deficiency in both
lamin A and
lamin C leads to slow growth,
muscle weakness, and death by 6 weeks of age. Fibroblasts deficient in
lamins A and C contain misshapen and structurally weakened nuclei, and
emerin is mislocalized away from the nuclear envelope. The physiologic rationale for the existence of the 2 different Lmna products
lamin A and
lamin C is unclear, although several reports have suggested that
lamin A may have particularly important functions, for example in the targeting of
emerin and
lamin C to the nuclear envelope. Here we report the development of
lamin C-only mice (Lmna(LCO/LCO)), which produce
lamin C but no
lamin A or
prelamin A (the precursor to
lamin A). Lmna(LCO/LCO) mice were entirely healthy, and Lmna(LCO/LCO) cells displayed normal
emerin targeting and exhibited only very minimal alterations in nuclear shape and nuclear deformability. Thus, at least in the mouse,
prelamin A and
lamin A appear to be dispensable. Nevertheless, an accumulation of farnesyl-
prelamin A (as occurs with a deficiency in the
prelamin A processing
enzyme Zmpste24) caused dramatically misshapen nuclei and
progeria-like disease phenotypes. The apparent dispensability of
prelamin A suggested that
lamin A-related progeroid syndromes might be treated with impunity by reducing
prelamin A synthesis. Remarkably, the presence of a single Lmna(LCO) allele eliminated the nuclear shape abnormalities and
progeria-like disease phenotypes in Zmpste24-/- mice. Moreover, treating Zmpste24-/- cells with a
prelamin A-specific
antisense oligonucleotide reduced
prelamin A levels and significantly reduced the frequency of misshapen nuclei. These studies suggest a new therapeutic strategy for treating
progeria and other
lamin A diseases.