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

@article{citeulike:239622, abstract = {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.}, address = {Department of Medicine, University of California, Los Angeles, CA 90095, USA. lfong@mednet.ucla.edu}, author = {Fong, L. G. and Ng, J. K. and Meta, M. and Cot\'{e}, N. and Yang, S. H. and Stewart, C. L. and Sullivan, T. and Burghardt, A. and Majumdar, S. and Reue, K. and Bergo, M. O. and Young, S. G.}, citeulike-article-id = {239622}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0408558102}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/15608054}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=15608054}, day = {28}, doi = {10.1073/pnas.0408558102}, issn = {0027-8424}, journal = {Proc Natl Acad Sci U S A}, month = {December}, number = {52}, pages = {18111--18116}, posted-at = {2005-06-28 21:11:18}, priority = {4}, title = {Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice.}, url = {http://dx.doi.org/10.1073/pnas.0408558102}, volume = {101}, year = {2004} }

TY - JOUR ID - citeulike:239622 L3 - citeulike-article-id:239622 N2 - 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. IS - 52 JF - Proc Natl Acad Sci U S A SN - 0027-8424 AD - Department of Medicine, University of California, Los Angeles, CA 90095, USA. lfong@mednet.ucla.edu EP - 18116 TI - Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice. VL - 101 SP - 18111 AU - Fong, LG AU - Ng, JK AU - Meta, M AU - Coté, N AU - Yang, SH AU - Stewart, CL AU - Sullivan, T AU - Burghardt, A AU - Majumdar, S AU - Reue, K AU - Bergo, MO AU - Young, SG PY - 2004/12/28/ UR - http://dx.doi.org/10.1073/pnas.0408558102 ER -