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Gene Review

ZMPSTE24  -  zinc metallopeptidase STE24

Homo sapiens

Synonyms: CAAX prenyl protease 1 homolog, FACE-1, FACE1, Farnesylated proteins-converting enzyme 1, HGPS, ...
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Disease relevance of ZMPSTE24

  • We now show compound heterozygous mutations, Phe361fsX379 and Trp340Arg, in the zinc metalloproteinase (ZMPSTE24) gene in one of the four patients who had severe MAD associated with progeroid appearance and generalized lipodystrophy [1].
  • CONCLUSIONS: The S573L homozygous LMNA mutation is associated with a novel phenotype of arthropathy, tendinous calcifications, and progeroid features distinct from the acroosteolysis previously reported in patients with mandibuloacral dysplasia caused by LMNA or ZMPSTE24 mutations [2].
  • A homozygous ZMPSTE24 null mutation in combination with a heterozygous mutation in the LMNA gene causes Hutchinson-Gilford progeria syndrome (HGPS): insights into the pathophysiology of HGPS [3].
  • Fluorescence in situ hybridization experiments showed that the human FACE-1 gene maps to 1p34, whereas FACE-2 is located at 11q13, a region frequently amplified in human carcinomas and lymphomas [4].
  • The identification of Ste24p homologues in a diverse group of organisms, including Escherichia coli, Schizosaccharomyces pombe, Haemophilus influenzae, and Homo sapiens, indicates that Ste24p has been highly conserved throughout evolution [5].

Psychiatry related information on ZMPSTE24

  • Knowing Your Place: Self-Perceptions of Status in Face-to-Face Groups [6].
  • Thirty-one infant siblings of children with autism and 24 comparison infants were tested at 6 months of age during social interaction with a caregiver, using a modified Still Face paradigm conducted via a closed-circuit TV-video system [7].

High impact information on ZMPSTE24

  • Whereas a-factor maturation appears relatively normal in the rce1Delta single mutant, the ste24Delta single mutant accumulates an intermediate that is correctly COOH terminally processed but is defective in cleavage of the NH2-terminal extension, demonstrating that Ste24p is also involved in NH2-terminal processing [8].
  • Consistent with our hypothesis, we find that expression in HeLa cells of GFP-progerin or an uncleavable form of prelamin A with a Zmpste24 cleavage site mutation induces the formation of abnormal nuclei similar to those in HGPS fibroblasts [9].
  • Thus, RD is either a primary or a secondary laminopathy, caused by dominant de novo LMNA mutations or, more frequently, recessive null ZMPSTE24 mutations, most of which lie in a mutation hotspot within exon 9 [10].
  • Their importance was supported by functional characterization of a PS mutant in which the face 1 and face 2 PS residues were reintroduced into Gla(FII)-PS, leading to significant APC cofactor activity, likely through restored interaction with APC [11].
  • A recently discovered component in a-factor processing is Ste24p/Afc1p, a multispanning endoplasmic reticulum membrane protein that contains an HEXXH metalloprotease motif [12].

Biological context of ZMPSTE24


Anatomical context of ZMPSTE24

  • As a consequence of the presumed lack of ZMPSTE24 activity, prelamin A, the unprocessed toxic form of lamin A, was detected in the nuclei of both cultured cells and tissue from RD patients, but not in control nuclei [16].
  • ZMPSTE24 encodes an enzyme necessary for the correct processing and maturation of lamin A, an intermediate filament component of the nuclear envelope [16].
  • The loss of body fat can also be caused by the premature death of adipocytes due to mutations in lamin A/C, nuclear lamina proteins, and ZMPSTE24, which modifies the prelamin A post-translationally [17].
  • Using antibodies that specifically recognise prelamin A, but not lamin A, we show that prelamin A accumulates at the nuclear lamina in FACE1 silenced cells, whereas in control cells prelamin A is found in many small nuclear dots, but not at the nuclear lamina [13].
  • Silencing of FACE1 in HL60, a cell line that lacks lamin A, also has no effect [13].

Associations of ZMPSTE24 with chemical compounds

  • Dual roles for Ste24p in yeast a-factor maturation: NH2-terminal proteolysis and COOH-terminal CAAX processing [8].
  • A membrane-associated metalloprotease of Taenia solium metacestode structurally related to the FACE-1/Ste24p protease family [18].
  • We used the Face Recognition Grand Challenge v2 database, yielding an average verification rate of 95.2 percent at 10-3 false accept rate [19].
  • Twins ranked their preference for five concentrations of sucrose/grape juice solutions (0.15-1.17M) with a Face Scale [20].
  • METHOD: Face-to-face interviews were conducted with a randomly selected sample of public housing tenants in the Hunter Region of New South Wales. RESULTS: Of 463 contactable tenants, 329 consented to participate in the study [21].
  • We also tested whether a new and chemically distinct HIV-PI, darunavir, inhibits ZMPSTE24 [22].

Other interactions of ZMPSTE24

  • Similarly, diverse human progeroid syndromes are caused by mutations in ZMPSTE24 or LMNA genes [23].
  • On the basis of these results, we suggest that inhibition of Face-1 and/or Face-2 could be part of strategies directed to block the functioning of prenylated proteins activated in oncogenic processes, including Ras proteins [4].

Analytical, diagnostic and therapeutic context of ZMPSTE24

  • Immunofluorescence analysis of epitope-tagged Hs Ste24p constructs suggested that it is localized in the ER and possibly also in the Golgi compartment [14].
  • Abstract Face and gaze processing were studied using magnetoencephalography in 10 children with autism and 10 normally developing children, aged between 7 and 12 years [24].
  • Cost-effectiveness of Mohs Micrographic Surgery vs Surgical Excision for Basal Cell Carcinoma of the Face [25].
  • METHOD: Face-to-face semi-structured interviews with 27 bereaved relatives to investigate their experience of terminal care and what their response had been to the sound of death rattle if this had occurred [26].
  • In 2000 a multidisciplinary protocol for weaning dysphagic patients from the tracheotomy tube and a decannulation decision chart created according to principles of the F.O.T.T.((R)) Concept (Face and Oral Tract Therapy) were introduced in the Swiss Neurological Rehabilitation Centre REHAB in Basel [27].


  1. Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Agarwal, A.K., Fryns, J.P., Auchus, R.J., Garg, A. Hum. Mol. Genet. (2003) [Pubmed]
  2. A homozygous mutation in the lamin A/C gene associated with a novel syndrome of arthropathy, tendinous calcinosis, and progeroid features. Van Esch, H., Agarwal, A.K., Debeer, P., Fryns, J.P., Garg, A. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  3. A homozygous ZMPSTE24 null mutation in combination with a heterozygous mutation in the LMNA gene causes Hutchinson-Gilford progeria syndrome (HGPS): insights into the pathophysiology of HGPS. Denecke, J., Brune, T., Feldhaus, T., Robenek, H., Kranz, C., Auchus, R.J., Agarwal, A.K., Marquardt, T. Hum. Mutat. (2006) [Pubmed]
  4. Identification and chromosomal location of two human genes encoding enzymes potentially involved in proteolytic maturation of farnesylated proteins. Freije, J.M., Blay, P., Pendás, A.M., Cadiñanos, J., Crespo, P., López-Otín, C. Genomics (1999) [Pubmed]
  5. A novel membrane-associated metalloprotease, Ste24p, is required for the first step of NH2-terminal processing of the yeast a-factor precursor. Fujimura-Kamada, K., Nouvet, F.J., Michaelis, S. J. Cell Biol. (1997) [Pubmed]
  6. Knowing Your Place: Self-Perceptions of Status in Face-to-Face Groups. Anderson, C., Srivastava, S., Beer, J.S., Spataro, S.E., Chatman, J.A. Journal of personality and social psychology (2006) [Pubmed]
  7. Visual Fixation Patterns during Reciprocal Social Interaction Distinguish a Subgroup of 6-Month-Old Infants At-Risk for Autism from Comparison Infants. Merin, N., Young, G.S., Ozonoff, S., Rogers, S.J. Journal of autism and developmental disorders (2007) [Pubmed]
  8. Dual roles for Ste24p in yeast a-factor maturation: NH2-terminal proteolysis and COOH-terminal CAAX processing. Tam, A., Nouvet, F.J., Fujimura-Kamada, K., Slunt, H., Sisodia, S.S., Michaelis, S. J. Cell Biol. (1998) [Pubmed]
  9. Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome. Mallampalli, M.P., Huyer, G., Bendale, P., Gelb, M.H., Michaelis, S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  10. Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursors. Navarro, C.L., Cadiñanos, J., De Sandre-Giovannoli, A., Bernard, R., Courrier, S., Boccaccio, I., Boyer, A., Kleijer, W.J., Wagner, A., Giuliano, F., Beemer, F.A., Freije, J.M., Cau, P., Hennekam, R.C., López-Otín, C., Badens, C., Lévy, N. Hum. Mol. Genet. (2005) [Pubmed]
  11. The gamma-carboxyglutamic acid domain of anticoagulant protein S is involved in activated protein C cofactor activity, independently of phospholipid binding. Saller, F., Villoutreix, B.O., Amelot, A., Kaabache, T., Le Bonniec, B.F., Aiach, M., Gandrille, S., Borgel, D. Blood (2005) [Pubmed]
  12. Reconstitution of the Ste24p-dependent N-terminal proteolytic step in yeast a-factor biogenesis. Schmidt, W.K., Tam, A., Michaelis, S. J. Biol. Chem. (2000) [Pubmed]
  13. RNAi of FACE1 protease results in growth inhibition of human cells expressing lamin A: implications for Hutchinson-Gilford progeria syndrome. Gruber, J., Lampe, T., Osborn, M., Weber, K. J. Cell. Sci. (2005) [Pubmed]
  14. Identification of a human cDNA encoding a novel protein structurally related to the yeast membrane-associated metalloprotease, Ste24p. Kumagai, H., Kawamura, Y., Yanagisawa, K., Komano, H. Biochim. Biophys. Acta (1999) [Pubmed]
  15. Activation of Preexisting and Acquired Face Representations: The N250 Event-related Potential as an Index of Face Familiarity. Tanaka, J.W., Curran, T., Porterfield, A.L., Collins, D. Journal of cognitive neuroscience. (2006) [Pubmed]
  16. Homozygous and compound heterozygous mutations in ZMPSTE24 cause the laminopathy restrictive dermopathy. Moulson, C.L., Go, G., Gardner, J.M., van der Wal, A.C., Smitt, J.H., van Hagen, J.M., Miner, J.H. J. Invest. Dermatol. (2005) [Pubmed]
  17. Genetic disorders of adipose tissue development, differentiation, and death. Agarwal, A.K., Garg, A. Annual review of genomics and human genetics (2006) [Pubmed]
  18. A membrane-associated metalloprotease of Taenia solium metacestode structurally related to the FACE-1/Ste24p protease family. Cai, G.B., Bae, Y.A., Kim, S.H., Na, B.K., Kim, T.S., Jiang, M.S., Kong, Y. Int. J. Parasitol. (2006) [Pubmed]
  19. Intraclass Retrieval of Nonrigid 3D Objects: Application to Face Recognition. Passalis, G., Kakadiaris, I.A., Theoharis, T. IEEE transactions on pattern analysis and machine intelligence (2007) [Pubmed]
  20. Heritability estimates for dental caries and sucrose sweetness preference. Bretz, W.A., Corby, P.M., Melo, M.R., Coelho, M.Q., Costa, S.M., Robinson, M., Schork, N.J., Drewnowski, A., Hart, T.C. Arch. Oral Biol. (2006) [Pubmed]
  21. Public housing, public health: health needs of public housing tenants. Wiggers, J., Radvan, D., Clover, K., Hazell, T., Alexander, J., Considine, R. Australian and New Zealand journal of public health. (2001) [Pubmed]
  22. A potent HIV protease inhibitor, darunavir, does not inhibit ZMPSTE24 or lead to an accumulation of farnesyl-prelamin A in cells. Coffinier, C., Hudon, S.E., Lee, R., Farber, E.A., Nobumori, C., Miner, J.H., Andres, D.A., Spielmann, H.P., Hrycyna, C.A., Fong, L.G., Young, S.G. J. Biol. Chem. (2008) [Pubmed]
  23. Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation. Varela, I., Cadiñanos, J., Pendás, A.M., Gutiérrez-Fernández, A., Folgueras, A.R., Sánchez, L.M., Zhou, Z., Rodríguez, F.J., Stewart, C.L., Vega, J.A., Tryggvason, K., Freije, J.M., López-Otín, C. Nature (2005) [Pubmed]
  24. Face- and gaze-sensitive neural responses in children with autism: a magnetoencephalographic study. Kylli??inen, A., Braeutigam, S., Hietanen, J.K., Swithenby, S.J., Bailey, A.J. Eur. J. Neurosci. (2006) [Pubmed]
  25. Cost-effectiveness of Mohs Micrographic Surgery vs Surgical Excision for Basal Cell Carcinoma of the Face. Essers, B.A., Dirksen, C.D., Nieman, F.H., Smeets, N.W., Krekels, G.A., Prins, M.H., Neumann, H.A. Archives of dermatology. (2006) [Pubmed]
  26. The sound of death rattle I: are relatives distressed by hearing this sound? Wee, B.L., Coleman, P.G., Hillier, R., Holgate, S.H. Palliative medicine. (2006) [Pubmed]
  27. Dysphagic patients with tracheotomies: a multidisciplinary approach to treatment and decannulation management. Frank, U., Mäder, M., Sticher, H. Dysphagia (2007) [Pubmed]
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