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

Szczegóły
Abstrakt

Tytuł:: Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice.
Autorzy:: Fong LG; Department of Medicine, University of California, Los Angeles, CA 90095, USA. />Ng JK
Meta M
Coté N
Yang SH
Stewart CL
Sullivan T
Burghardt A
Majumdar S
Reue K
Bergo MO
Young SG
Źródło:: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2004 Dec 28; Vol. 101 (52), pp. 18111-6. Date of Electronic Publication: 2004 Dec 17.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.
Język:: English
Imprint Name(s):: Original Publication: Washington, DC : National Academy of Sciences
MeSH Terms:: Heterozygote*
Lamins/*genetics
Lipoproteins/*genetics
Membrane Proteins/*genetics
Metalloendopeptidases/*genetics
Metalloproteases/*genetics
Progeria/*genetics
Alleles ; Animals ; Blotting, Western ; Cell Nucleus/metabolism ; Cell Proliferation ; Cells, Cultured ; Coloring Agents/pharmacology ; Female ; Fibroblasts/metabolism ; Fluorescent Dyes/pharmacology ; Humans ; Lamin Type A ; Lasers ; Mice ; Mice, Knockout ; Mice, Transgenic ; Microscopy, Fluorescence ; Muscles/pathology ; Nuclear Proteins/metabolism ; Organic Chemicals ; Phenotype ; Progeria/pathology ; Protein Precursors/metabolism ; Skull/abnormalities ; Skull/pathology ; Time Factors ; Tomography, X-Ray Computed
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Grant Information:: R01 AR050200 United States AR NIAMS NIH HHS; R01 HL076839 United States HL NHLBI NIH HHS; AR050200 United States AR NIAMS NIH HHS; HL076839 United States HL NHLBI NIH HHS
Substance Nomenclature:: 0 (Coloring Agents)
0 (Fluorescent Dyes)
0 (LMNA protein, human)
0 (Lamin Type A)
0 (Lamins)
0 (Lipoproteins)
0 (Membrane Proteins)
0 (Nuclear Proteins)
0 (Organic Chemicals)
0 (Protein Precursors)
0 (SYTOX Green)
0 (prelamin A)
EC 3.4.- (Metalloproteases)
EC 3.4.24.- (Metalloendopeptidases)
EC 3.4.24.- (Zmpste24 protein, mouse)
EC 3.4.24.84 (ZMPSTE24 protein, human)
Entry Date(s):: Date Created: 20041221 Date Completed: 20050228 Latest Revision: 20240314
Update Code:: 20240314
PubMed Central ID:: PMC536056
DOI:: 10.1073/pnas.0408558102
PMID:: 15608054
: Czasopismo naukowe

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.

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