Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice

Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18111-6. doi: 10.1073/pnas.0408558102. Epub 2004 Dec 17.

Abstract

Zmpste24 is a metalloproteinase required for the processing of prelamin A to lamin A, a structural component of the nuclear lamina. Zmpste24 deficiency results in the accumulation of prelamin A within cells, a complete loss of mature lamin A, and misshapen nuclear envelopes. Zmpste24-deficient (Zmpste24(-/-)) mice exhibit retarded growth, alopecia, micrognathia, dental abnormalities, osteolytic lesions in bones, and osteoporosis, which are phenotypes shared with Hutchinson-Gilford progeria syndrome, a human disease caused by the synthesis of a mutant prelamin A that cannot undergo processing to lamin A. Zmpste24(-/-) mice also develop muscle weakness. We hypothesized that prelamin A might be toxic and that its accumulation in Zmpste24(-/-) mice is responsible for all of the disease phenotypes. We further hypothesized that Zmpste24(-/-) mice with half-normal levels of prelamin A (Zmpste24(-/-) mice with one Lmna knockout allele) would be subjected to less toxicity and be protected from disease. Thus, we bred and analyzed Zmpste24(-/-)Lmna(+/-) mice. As expected, prelamin A levels in Zmpste24(-/-)Lmna(+/-) cells were significantly reduced. Zmpste24(-/-)Lmna(+/-) mice were entirely normal, lacking all disease phenotypes, and misshapen nuclei were less frequent in Zmpste24(-/-)Lmna(+/-) cells than in Zmpste24(-/-) cells. These data suggest that prelamin A is toxic and that reducing its levels by as little as 50% provides striking protection from disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Blotting, Western
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Coloring Agents / pharmacology
  • Female
  • Fibroblasts / metabolism
  • Fluorescent Dyes / pharmacology
  • Heterozygote*
  • Humans
  • Lamin Type A
  • Lamins / genetics*
  • Lasers
  • Lipoproteins / genetics*
  • Membrane Proteins / genetics*
  • Metalloendopeptidases / genetics*
  • Metalloproteases / genetics*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Muscles / pathology
  • Nuclear Proteins / metabolism
  • Organic Chemicals
  • Phenotype
  • Progeria / genetics*
  • Progeria / pathology
  • Protein Precursors / metabolism
  • Skull / abnormalities
  • Skull / pathology
  • Time Factors
  • Tomography, X-Ray Computed

Substances

  • Coloring Agents
  • Fluorescent Dyes
  • LMNA protein, human
  • Lamin Type A
  • Lamins
  • Lipoproteins
  • Membrane Proteins
  • Nuclear Proteins
  • Organic Chemicals
  • Protein Precursors
  • SYTOX Green
  • prelamin A
  • Metalloproteases
  • Metalloendopeptidases
  • Zmpste24 protein, mouse
  • ZMPSTE24 protein, human