Loren G. Fong1, Jennifer K. Ng1,2, Margarita Meta1,3, Nathan Coté1, Shao H. Yang1, Colin L. Stewart1,2, Terry Sullivan1,2, Andrew J. Burghardt1, Sharmila Majumdar1, Karen Reue1, Martin O. Bergö1, Stephen G. Young1,3
1Department of Medicine, University of California, Los Angeles, CA 90095; Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94141-9100; National Cancer Institute, Frederick, MD 21702; and Musculoskeletal and Quantitative Research Group, Department of Radiology, University of California, San Francisco, CA 94107
2National Institutes of Health, Bethesda, MD
3National Cancer Institute, Frederick, MD 21702;
Tóm tắt
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.
