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

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.

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Cell- och molekylärbiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Cell and Molecular Biology hsv//eng
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

Ng, J. K. (författare)
Meta, M. (författare)
Cote, N. (författare)
Yang, S. H. (författare)
Stewart, C. L. (författare)
Sullivan, T. (författare)
Burghardt, A. (författare)
Majumdar, S. (författare)
Reue, K. (författare)
Bergö, Martin,1970Gothenburg University,Göteborgs universitet,Institutionen för invärtesmedicin,Institute of Internal Medicine(Swepub:gu)xbmarl (författare)
Young, S. G. (författare)
Göteborgs universitetInstitutionen för invärtesmedicin (creator_code:org_t)

Av författaren/redakt...: Fong, L. G.; Ng, J. K.; Meta, M.; Cote, N.; Yang, S. H.; Stewart, C. L.; visa fler...; Sullivan, T.; Burghardt, A.; Majumdar, S.; Reue, K.; Bergö, Martin, 1 ...; Young, S. G.; visa färre...

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