Prelamin A and lamin A appear to be dispensable in the nuclear lamina
Loren G. Fong, … , Martin O. Bergo, Stephen G. Young
Loren G. Fong, … , Martin O. Bergo, Stephen G. Young
Published March 1, 2006
Citation Information: J Clin Invest. 2006;116(3):743-752. https://doi.org/10.1172/JCI27125.
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Research Article Genetics

Prelamin A and lamin A appear to be dispensable in the nuclear lamina

Abstract

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+/+), which produce lamin C but no lamin A or prelamin A (the precursor to lamin A). Lmna+/+ mice were entirely healthy, and Lmna+/+ 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 LmnaLCO 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.

Authors

Loren G. Fong, Jennifer K. Ng, Jan Lammerding, Timothy A. Vickers, Margarita Meta, Nathan Coté, Bryant Gavino, Xin Qiao, Sandy Y. Chang, Stephanie R. Young, Shao H. Yang, Colin L. Stewart, Richard T. Lee, C. Frank Bennett, Martin O. Bergo, Stephen G. Young

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Growth rates, grip strength, and survival of Zmpste24 –/ –LmnaLCO/+ and ...
Growth rates, grip strength, and survival of Zmpste24 –/ –LmnaLCO/+ and Zmpste24 –/ – mice. Compound heterozygotes (Zmpste24+/ –LmnaLCO/+) were intercrossed to generate littermate Zmpste24 –/ –LmnaLCO/+ and Zmpste24 –/ –Lmna+/+ mice. (A) The growth rate of male Zmpste24 –/ – mice (n = 4) was retarded, whereas Zmpste24 –/ –LmnaLCO/+ mice (n = 5) exhibited normal growth indistinguishable from that of wild-type mice (n = 7). Similar results were obtained with male Zmpste24 –/ –Lmna+/+ mice (not shown). (B) Grip strength in 17-week-old wild-type (n = 7), Zmpste24 –/ – (n = 4), and Zmpste24 –/ –LmnaLCO/+ mice (n = 5), as judged by the length of time that they were able to hang upside-down from a grid (14). P < 0.001, t test, Zmpste24 –/ – versus Zmpste24 –/ –LmnaLCO/+. (C) The survival rates were followed over a 30-week period. By 26 weeks of age, all of the Zmpste24 –/ – mice had died (or were euthanized at the request of the veterinary staff). In contrast, all of the Zmpste24 –/ – mice with a single LmnaLCO allele were alive and exhibiting normal health. n = 6 mice per group.