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.
Fong
Loren G
LG
Department of Medicine, University of California, Los Angeles, CA 90095, USA. lfong@mednet.ucla.edu
Ng
Jennifer K
JK
Meta
Margarita
M
Coté
Nathan
N
Yang
Shao H
SH
Stewart
Colin L
CL
Sullivan
Terry
T
Burghardt
Andrew
A
Majumdar
Sharmila
S
Reue
Karen
K
Bergo
Martin O
MO
Young
Stephen G
SG
D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004396:Coloring Agents / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005456:Fluorescent Dyes / Q000494:pharmacology; D006579:Heterozygote; D006801:Humans; D034904:Lamin Type A; D034882:Lamins / Q000235:genetics*; D007834:Lasers; D008074:Lipoproteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008666:Metalloendopeptidases / Q000235:genetics*; D045726:Metalloproteases / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009132:Muscles / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D009930:Organic Chemicals; D010641:Phenotype; D011371:Progeria / Q000235:genetics* / Q000473:pathology; D011498:Protein Precursors / Q000378:metabolism; D012886:Skull / Q000002:abnormalities / Q000473:pathology; D013997:Time Factors; D014057:Tomography, X-Ray Computed
D004396:Coloring Agents; D005456:Fluorescent Dyes; C494847:LMNA protein, human; D034904:Lamin Type A; D034882:Lamins; D008074:Lipoproteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D009930:Organic Chemicals; D011498:Protein Precursors; C402795:SYTOX Green; C090764:prelamin A; D045726:Metalloproteases; D008666:Metalloendopeptidases; C491250:Zmpste24 protein, mouse; C120130:ZMPSTE24 protein, human