WFRF:(Stewart K. M.)
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Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice
- Fong, L. G. (author)
- Ng, J. K. (author)
- Meta, M. (author)
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- Cote, N. (author)
- Yang, S. H. (author)
- Stewart, C. L. (author)
- Sullivan, T. (author)
- Burghardt, A. (author)
- Majumdar, S. (author)
- Reue, K. (author)
- Young, S. G. (author)
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- (creator_code:org_t)
- 2004
- 2004
- English.
- In: Proc Natl Acad Sci U S A. ; 101:52, s. 18111-18116
- Journal article (peer-reviewed)
Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- CAAX proteiner
- prelamin A
- lamin A
- djurmodeller
- genteknik
- Alleles
- Animals
- Blotting
- Western
- Cell Nucleus/metabolism
- Cell Proliferation
- Cells
- Cultured
- Dyes/pharmacology
- Female
- Fibroblasts/metabolism
- Fluorescent Dyes/pharmacology
- *Heterozygote
- Humans
- Lamins/*genetics
- Lasers
- Lipoproteins/*genetics
- Membrane Proteins/*genetics
- Metalloendopeptidases/*genetics
- Metalloproteases/*genetics
- Mice
- Mice
- Knockout
- Mice
- Transgenic
- Microscopy
- Fluorescence
- Muscles/pathology
- Nuclear Proteins/metabolism
- Phenotype
- Progeria/*genetics/pathology
- Protein Precursors/metabolism
- Research Support
- Non-U.S. Gov't
- Research Support
- U.S. Gov't
- P.H.S.
- Skull/abnormalities/pathology
- Time Factors
- Tomography
- X-Ray Computed
Publication and Content Type
- ref (subject category)
- art (subject category)
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- Fong, L. G.
- Ng, J. K.
- Meta, M.
- Cote, N.
- Yang, S. H.
- Stewart, C. L.
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- Sullivan, T.
- Burghardt, A.
- Majumdar, S.
- Reue, K.
- Bergö, Martin, 1 ...
- Young, S. G.
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
- MEDICAL AND HEAL ...
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- University of Gothenburg
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