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Heterozygosity for ...
Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice
- Article/chapterEnglish2004
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LIBRIS-ID:oai:gup.ub.gu.se/55229
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https://gup.ub.gu.se/publication/55229URI
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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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 and genre
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MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Cell- och molekylärbiologi hsv//swe
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MEDICAL AND HEALTH SCIENCES Basic Medicine Cell and Molecular Biology hsv//eng
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CAAX proteiner
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prelamin A
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lamin A
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djurmodeller
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genteknik
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Alleles
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Animals
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Blotting
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Western
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Cell Nucleus/metabolism
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Cell Proliferation
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Cells
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Cultured
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Dyes/pharmacology
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Female
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Fibroblasts/metabolism
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Fluorescent Dyes/pharmacology
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*Heterozygote
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Humans
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Lamins/*genetics
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Lasers
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Lipoproteins/*genetics
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Membrane Proteins/*genetics
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Metalloendopeptidases/*genetics
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Metalloproteases/*genetics
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Mice
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Mice
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Knockout
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Mice
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Transgenic
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Microscopy
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Fluorescence
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Muscles/pathology
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Nuclear Proteins/metabolism
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Phenotype
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Progeria/*genetics/pathology
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Protein Precursors/metabolism
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Research Support
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Non-U.S. Gov't
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Research Support
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U.S. Gov't
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P.H.S.
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Skull/abnormalities/pathology
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Time Factors
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Tomography
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X-Ray Computed
Added entries (persons, corporate bodies, meetings, titles ...)
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Ng, J. K.
(author)
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Meta, M.
(author)
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Cote, N.
(author)
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Yang, S. H.
(author)
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Stewart, C. L.
(author)
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Sullivan, T.
(author)
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Burghardt, A.
(author)
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Majumdar, S.
(author)
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Reue, K.
(author)
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Bergö, Martin,1970Gothenburg University,Göteborgs universitet,Institutionen för invärtesmedicin,Institute of Internal Medicine(Swepub:gu)xbmarl
(author)
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Young, S. G.
(author)
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Göteborgs universitetInstitutionen för invärtesmedicin
(creator_code:org_t)
Related titles
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In:Proc Natl Acad Sci U S A101:52, s. 18111-18116
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Fong, L. G.
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Ng, J. K.
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Meta, M.
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Cote, N.
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Yang, S. H.
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Stewart, C. L.
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Sullivan, T.
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Burghardt, A.
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Majumdar, S.
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Reue, K.
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Bergö, Martin, 1 ...
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Young, S. G.
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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University of Gothenburg