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

Nature Genetics volume 31, pages 94–99 (2002)Cite this article

Abstract

The mouse ortholog of human FACE-1, Zmpste24, is a multispanning membrane protein widely distributed in mammalian tissues1,2 and structurally related to Afc1p/ste24p, a yeast metalloproteinase involved in the maturation of fungal pheromones3. 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 lamin4, a major component of the nuclear lamina5, and phenocopy most defects observed in humans with diverse congenital laminopathies6,7,8. 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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Figure 1: Generation of Zmpste24-deficient mice.
Figure 2: Expression analysis of Zmpste24 during mouse development and in adult tissues.
Figure 3: Histology of heart, liver and muscle from Zmpste24-null (left) and wildtype (right) mice.
Figure 4: Masson trichrome staining of skin and subcutaneous tissue, showing lypodystrophy.
Figure 5: Loss of Zmpste24 prevents prelamin A processing.
Figure 6: Nuclear envelope architecture in wildtype and Zmpste24-deficient cells.

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Acknowledgements

We thank A.A. Ferrando, M. Serrano, D. Langenau, A. Fueyo, M. Balbín, G. Velasco, S. Cal, J.A. Uría and L.M. Sánchez for helpful comments; T. Look for support and advice; G. Morris, P. Crespo and K. Iwata for providing reagents; F. Alvarez for help in biochemical analysis and T. Sánchez, M. Fernández, U. Mikkonen and J. Wilbertz for excellent technical assistance. This work was supported by Comisión Interministerial de Ciencia y Tecnología, Fondos Plan FEDER, European Union, The Novo Nordisk Foundation, Swedish Medical Research Council and the Swedish Cancer Foundation. J.C. is the recipient of a fellowship from Gobierno Vasco (Spain). J.W. is a recipient of a Karolinska Institute Postdoc fellowship. The Instituto Universitario de Oncología is supported by Obra Social Cajastur-Asturias, Spain.

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  1. Alberto M. Pendás, Zhongjun Zhou and Juan Cadiñanos: These authors contributed equally to this work.

Authors and Affiliations

  1. Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, 33006, Spain

    Alberto M. Pendás, Juan Cadiñanos, José M.P. Freije, Francisco Rodríguez & Carlos López-Otín

  2. Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    Zhongjun Zhou, Jianming Wang & Karl Tryggvason

  3. Department of Pathology, Karolinska Institutet, Huddinge University Hospital, Huddinge, Sweden

    Kjell Hultenby & Annika Wernerson

  4. Servicio de Anatomía Patológica, Hospital Central de Asturias, Oviedo, Spain

    Aurora Astudillo

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  1. Alberto M. Pendás
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Correspondence to Carlos López-Otín.

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Pendás, A., Zhou, Z., Cadiñanos, J. et al. Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase–deficient mice. Nat Genet 31, 94–99 (2002). https://doi.org/10.1038/ng871

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