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- Title
Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase?deficient mice.
- Authors
Pendás, Alberto M.; Zhou, Zhongjun; Cadiñanos, Juan; Freije, José M.P.; Wang, Jianming; Hultenby, Kjell; Astudillo, Aurora; Wernerson, Annika; Rodríguez, Francisco; Tryggvason, Karl; López-Otín, Carlos
- Abstract
The mouse ortholog of human FACE-l, Zmpste24, is a multispanning membrane protein widely distributed in mammalian tissues and structurally related to Afc1p/ste24p, a yeast metalloproteinase involved in the maturation of fungal pheromones. Disruption of the gene Zmpste24 caused severe growth retardation and premature death in homozygous-null mice. Histopathological analysis of the mutant mice revealed several abnormalities, including dilated cardiomyopathy, muscular dystrophy and lipodystrophy. These alterations are similar to those developed by mice deficient in A-type lamin, a major component of the nuclear lamina, and phenocopy most defects observed in humans with diverse congenital laminopathies. In agreement with this finding, Zmpste24-null mice are defective in the proteolytic processing of prelamin A. This deficiency in prelamin A maturation leads to the generation of abnormalities in nuclear architecture that probably underlie the many phenotypes observed in both mice and humans with mutations in the lamin A gene. These results indicate that prelamin A is a specific substrate for Zmpste24 and demonstrate the usefulness of genetic approaches for identifying the in vivo substrates of proteolytic enzymes.
- Subjects
FAT cells; METALLOPROTEINASES
- Publication
Nature Genetics, 2002, Vol 31, Issue 1, p94
- ISSN
1061-4036
- Publication type
Article