Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 116, Issue 3, Pages 743-752Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI27125
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Funding
- NCI NIH HHS [R01 CA099506, CA099506] Funding Source: Medline
- NHLBI NIH HHS [R01 HL082792] Funding Source: Medline
- NIAID NIH HHS [R01 AI054384, AI054384] Funding Source: Medline
- NIAMS NIH HHS [AR050200, R01 AR050200] Funding Source: Medline
- NINDS NIH HHS [R01 NS059348] Funding Source: Medline
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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.
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