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

http://www.ncbi.nlm.nih.gov/pubmed/16511604

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.

Pubmed ID: 16511604 RIS Download

Mesh terms: Animals | Cell Line, Transformed | Cells, Cultured | Female | Fibroblasts | Lamin Type A | Mice | Mice, Inbred C57BL | Mice, Knockout | Mice, Transgenic | Muscle Weakness | Nuclear Lamina | Nuclear Proteins | Protein Isoforms | Protein Precursors | RNA, Messenger | Skull | Spine

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Associated grants

  • Agency: NIAID NIH HHS, Id: AI054384
  • Agency: NIAMS NIH HHS, Id: AR050200
  • Agency: NCI NIH HHS, Id: CA099506
  • Agency: NHLBI NIH HHS, Id: R01 HL082792
  • Agency: NINDS NIH HHS, Id: R01 NS059348

Mouse Genome Informatics (Data, Gene Annotation)

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