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(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.

• 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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 116 Issue 3 Pg. 743-52 (Mar 2006) ISSN: 0021-9738 [Print] United States
• PMID: 16511604 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Lamin Type A
• Nuclear Proteins
• Protein Isoforms
• Protein Precursors
• RNA, Messenger
• lamin C
• prelamin A

Topics

• Animals
• Cell Line, Transformed
• Cells, Cultured
• Female
• Fibroblasts (metabolism)
• Lamin Type A (deficiency, genetics, metabolism, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Muscle Weakness (genetics)
• Nuclear Lamina (physiology)
• Nuclear Proteins (genetics, physiology)
• Protein Isoforms (genetics, metabolism)
• Protein Precursors (genetics, physiology)
• RNA, Messenger (metabolism)
• Skull (abnormalities)
• Spine (abnormalities)