Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice

被引:431
作者
Pendás, AM
Zhou, ZJ
Cadiñanos, J
Freije, JMP
Wang, JM
Hultenby, K
Astudillo, A
Wernerson, A
Rodríguez, F
Tryggvason, K
López-Otín, C [1 ]
机构
[1] Univ Oviedo, Inst Univ Oncol, Fac Med, Dept Bioquim & Biol Mol, E-33006 Oviedo, Spain
[2] Karolinska Inst, Dept Med Biochem & Biophys, Div Matrix Biol, Stockholm, Sweden
[3] Huddinge Univ Hosp, Karolinska Inst, Dept Pathol, S-14186 Huddinge, Sweden
[4] Univ Oviedo, Hosp Cent Asturias, Serv Anat Patol, E-33080 Oviedo, Spain
关键词
D O I
10.1038/ng871
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
The mouse ortholog of human FACE-1, Zmpste24, is a multi-spanning membrane protein widely distributed in mammalian tissues(1,2) and structurally related to Afc1p/ste24p, a yeast metalloproteinase involved in the maturation of fungal pheromones(3). 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(4), a major component of the nuclear lamina(5), and phenocopy most defects observed in humans with diverse congenital laminopathies(6-8). 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.
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页码:94 / 99
页数:6
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