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

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

Authors

  • Fong LG
  • Ng JK
  • Lammerding J
  • Vickers TA
  • Meta M
  • Coté N
  • Gavino B
  • Qiao X
  • Chang SY
  • Young SR
  • Yang SH
  • Stewart CL
  • Lee RT
  • Bennett CF
  • Bergo MO
  • Young SG

Journal

The Journal of clinical investigation

Publication Data

March 2, 2006

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

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