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Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice.

The mouse ortholog of human FACE-1, Zmpste24, is a multispanning membrane protein widely distributed in mammalian tissues and structurally related to Afc1p/ste24p, a yeast metalloproteinase involved in the maturation of fungal pheromones. Disruption of the gene Zmpste24 caused severe growth retardation and premature death in homozygous-null mice. Histopathological analysis of the mutant mice revealed several abnormalities, including dilated cardiomyopathy, muscular dystrophy and lipodystrophy. These alterations are similar to those developed by mice deficient in A-type lamin, a major component of the nuclear lamina, and phenocopy most defects observed in humans with diverse congenital laminopathies. In agreement with this finding, Zmpste24-null mice are defective in the proteolytic processing of prelamin A. This deficiency in prelamin A maturation leads to the generation of abnormalities in nuclear architecture that probably underlie the many phenotypes observed in both mice and humans with mutations in the lamin A gene. These results indicate that prelamin A is a specific substrate for Zmpste24 and demonstrate the usefulness of genetic approaches for identifying the in vivo substrates of proteolytic enzymes.

Pubmed ID: 11923874

Authors

  • Pendás AM
  • Zhou Z
  • Cadiñanos J
  • Freije JM
  • Wang J
  • Hultenby K
  • Astudillo A
  • Wernerson A
  • Rodríguez F
  • Tryggvason K
  • López-Otín C

Journal

Nature genetics

Publication Data

May 1, 2002

Associated Grants

None

Mesh Terms

  • Adipocytes
  • Animals
  • Cell Nucleus
  • Female
  • Humans
  • Male
  • Membrane Proteins
  • Metalloendopeptidases
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscles
  • Myocardium
  • Nuclear Proteins
  • Phenotype
  • Protein Precursors
  • Protein Processing, Post-Translational