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Gene Review

CSTB  -  cystatin B (stefin B)

Homo sapiens

Synonyms: CPI-B, CST6, Cystatin-B, EPM1, EPM1A, ...
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Disease relevance of CSTB


Psychiatry related information on CSTB


High impact information on CSTB

  • Loss-of-function mutations in the gene (CSTB) encoding human cystatin B, a widely expressed cysteine protease inhibitor, are responsible for a severe neurological disorder known as Unverricht-Lundborg disease (EPM1) [8].
  • Progressive myoclonus epilepsy type 1 (EPM1, also known as Unverricht-Lundborg disease) is an autosomal recessive disorder characterized by progressively worsening myoclonic jerks, frequent generalized tonic-clonic seizures, and a slowly progressive decline in cognition [9].
  • Unstable insertion in the 5' flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1 [9].
  • The size of the insertion varies between different EPM1 chromosomes sharing a common haplotype and a common origin, suggesting some level of meiotic instability over the course of many generations [9].
  • Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1 [10].

Chemical compound and disease context of CSTB


Biological context of CSTB

  • However, the Baltic haplotype, A3 (5-1-1-A-1-1), was observed in ten WEC ULDc (20.8%) and the CSTB 3'UTR variant, which we called the Alps variant, was observed in 17 ULDc (35.4%) [16].
  • This minisatellite repeat expansion, located in the putative promoter of CSTB 175 bp upstream from the translation initiation codon, appears to downregulate CSTB gene expression in vivo [17].
  • Transient transfections of cultured mammalian cells suggest that the region from -670 to -1 bp from the translation initiation codon functions as the CSTB promoter [17].
  • Amino acid sequence determination revealed the presence of stefin A and stefin B type inhibitors and two new inhibitors, designated as porcine stefin D1 and stefin D2 [18].
  • Its physiological function and the molecular pathways leading to the clinical EPM1 phenotype are unknown [19].

Anatomical context of CSTB


Associations of CSTB with chemical compounds


Physical interactions of CSTB

  • Comparison with the X-ray structure of cystatin B in the papain complex shows that the conformation of the first binding loop is quite similar to that of cystatin A, with an rms deviation of 0.78 A for the backbone atoms in the 43-53 region (cystatin A numbering) [27].
  • A model of the tertiary structure of cathepsin H and its complex with stefin B was constructed [28].

Regulatory relationships of CSTB


Other interactions of CSTB

  • In fact, cystatin B is found mainly in the nucleus of proliferating cells and both in the nucleus and in the cytoplasm of differentiated cells, while cathepsin B, in either case, is essentially cytoplasmic [1].
  • Stefin A is composed of 101 amino acids and has an Mr of 11 391 while stefin B contains 98 amino acids, has an Mr of 11 174 and is N-terminally blocked [18].
  • Unverricht-Lundborg disease (ULD) is a progressive myoclonus epilepsy common in Finland and North Africa, and less common in Western Europe. ULD is mostly caused by expansion of a dodecamer repeat in the cystatin B gene ( CSTB) promoter [16].
  • The EPM1 locus was mapped to within 0.3 cM from PFKL in chromosome 21q22 [2].
  • The gene for Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) has previously been mapped by linkage to markers on chromosome 21q22 [30].

Analytical, diagnostic and therapeutic context of CSTB

  • Confocal microscopy analysis of the subcellular localization of cystatin B and cathepsin B shows that, in vivo, the two proteins are concentrated in different cell compartments [1].
  • To provide new insights into the biochemical and pathological mechanisms of EPM1, we are working toward developing an animal model for this disease [31].
  • The formation of inactive complexes in excess molar amounts of human cathepsins H and L with their protein inhibitors human stefin A, human stefin B and chicken cystatin at pH 5.6 has been shown by measurement of enzyme activity coupled with reverse-phase HPLC not to involve covalent cleavage of the inhibitors [32].
  • We used alkaline treatment, affinity chromatography on Cm-papain Sepharose, followed by gel filtration and ion-exchange chromatography and anti-Stefin B-Sepharose 4B to isolate two major isoforms of Stefin B with pI values 5.9 and 6 [33].
  • 5. M(r) of ovarian Stefin B was close to 14,000 as judged by SDS-PAGE and had a blocked N-terminus [33].


  1. Nuclear localization of cystatin B, the cathepsin inhibitor implicated in myoclonus epilepsy (EPM1). Riccio, M., Di Giaimo, R., Pianetti, S., Palmieri, P.P., Melli, M., Santi, S. Exp. Cell Res. (2001) [Pubmed]
  2. Identification of mutations in cystatin B, the gene responsible for the Unverricht-Lundborg type of progressive myoclonus epilepsy (EPM1). Lalioti, M.D., Mirotsou, M., Buresi, C., Peitsch, M.C., Rossier, C., Ouazzani, R., Baldy-Moulinier, M., Bottani, A., Malafosse, A., Antonarakis, S.E. Am. J. Hum. Genet. (1997) [Pubmed]
  3. Cysteine proteinase inhibitors stefin A, stefin B, and cystatin C in sera from patients with colorectal cancer: relation to prognosis. Kos, J., Krasovec, M., Cimerman, N., Nielsen, H.J., Christensen, I.J., Brünner, N. Clin. Cancer Res. (2000) [Pubmed]
  4. Cloning a synthetic gene for human stefin B and its expression in E. coli. Jerala, R., Trstenjak, M., Lenarcic, B., Turk, V. FEBS Lett. (1988) [Pubmed]
  5. Expression of cystatins, high molecular weight cytokeratin, and proliferation markers in prostatic adenocarcinoma and hyperplasia. Mirtti, T., Alanen, K., Kallajoki, M., Rinne, A., Söderström, K.O. Prostate (2003) [Pubmed]
  6. Identification of cystatin B as a potential serum marker in hepatocellular carcinoma. Lee, M.J., Yu, G.R., Park, S.H., Cho, B.H., Ahn, J.S., Park, H.J., Song, E.Y., Kim, D.G. Clin. Cancer Res. (2008) [Pubmed]
  7. Conformational changes preceding amyloid-fibril formation of amyloid-beta and stefin B; parallels in pH dependence. Matsunaga, Y., Ierovnik, E., Yamada, T., Turk, V. Current medicinal chemistry. (2002) [Pubmed]
  8. Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice. Pennacchio, L.A., Bouley, D.M., Higgins, K.M., Scott, M.P., Noebels, J.L., Myers, R.M. Nat. Genet. (1998) [Pubmed]
  9. Unstable insertion in the 5' flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1. Lafrenière, R.G., Rochefort, D.L., Chrétien, N., Rommens, J.M., Cochius, J.I., Kälviäinen, R., Nousiainen, U., Patry, G., Farrell, K., Söderfeldt, B., Federico, A., Hale, B.R., Cossio, O.H., Sørensen, T., Pouliot, M.A., Kmiec, T., Uldall, P., Janszky, J., Pranzatelli, M.R., Andermann, F., Andermann, E., Rouleau, G.A. Nat. Genet. (1997) [Pubmed]
  10. Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1. Virtaneva, K., D'Amato, E., Miao, J., Koskiniemi, M., Norio, R., Avanzini, G., Franceschetti, S., Michelucci, R., Tassinari, C.A., Omer, S., Pennacchio, L.A., Myers, R.M., Dieguez-Lucena, J.L., Krahe, R., de la Chapelle, A., Lehesjoki, A.E. Nat. Genet. (1997) [Pubmed]
  11. Structure-antiviral activity relationship in the series of pyrimidine and purine N-[2-(2-phosphonomethoxy)ethyl] nucleotide analogues. 1. Derivatives substituted at the carbon atoms of the base. Holý, A., Günter, J., Dvoráková, H., Masojídková, M., Andrei, G., Snoeck, R., Balzarini, J., De Clercq, E. J. Med. Chem. (1999) [Pubmed]
  12. Metabolic myopathy in canine muscle-type phosphofructokinase deficiency. Giger, U., Argov, Z., Schnall, M., Bank, W.J., Chance, B. Muscle Nerve (1988) [Pubmed]
  13. Superoxide dismutase and glutathione peroxidase function in progressive myoclonus epilepsies. Ben-Menachem, E., Kyllerman, M., Marklund, S. Epilepsy Res. (2000) [Pubmed]
  14. L-tryptophan-carbidopa trial in patients with long-standing progressive myoclonus epilepsy. Leino, E., MacDonald, E., Airaksinen, M.M., Riekkinen, P.J., Salo, H. Acta neurologica Scandinavica. (1981) [Pubmed]
  15. Sensitization of chronic myeloid leukemia cells to adriamycin cytotoxicity by clofibrate. Parekh, H., Satyamoorthy, K., Advani, S., Chitnis, M. Tumori. (1990) [Pubmed]
  16. Haplotype study of West European and North African Unverricht-Lundborg chromosomes: evidence for a few founder mutations. Moulard, B., Genton, P., Grid, D., Jeanpierre, M., Ouazzani, R., Mrabet, A., Morris, M., LeGuern, E., Dravet, C., Mauguière, F., Utermann, B., Baldy-Moulinier, M., Belaidi, H., Bertran, F., Biraben, A., Ali Chérif, A., Chkili, T., Crespel, A., Darcel, F., Dulac, O., Geny, C., Humbert-Claude, V., Kassiotis, P., Buresi, C., Malafosse, A. Hum. Genet. (2002) [Pubmed]
  17. Characterization of the cystatin B gene promoter harboring the dodecamer repeat expanded in progressive myoclonus epilepsy, EPM1. Alakurtti, K., Virtaneva, K., Joensuu, T., Palvimo, J.J., Lehesjoki, A.E. Gene (2000) [Pubmed]
  18. Differences in specificity for the interactions of stefins A, B and D with cysteine proteinases. Lenarcic, B., Krizaj, I., Zunec, P., Turk, V. FEBS Lett. (1996) [Pubmed]
  19. Reduced cystatin B activity correlates with enhanced cathepsin activity in progressive myoclonus epilepsy. Rinne, R., Saukko, P., Järvinen, M., Lehesjoki, A.E. Ann. Med. (2002) [Pubmed]
  20. Role of cathepsins and cystatins in patients with recurrent miscarriage. Nakanishi, T., Ozaki, Y., Blomgren, K., Tateyama, H., Sugiura-Ogasawara, M., Suzumori, K. Mol. Hum. Reprod. (2005) [Pubmed]
  21. Human cystatins in normal and diseased tissues--a review. Järvinen, M., Rinne, A., Hopsu-Havu, V.K. Acta Histochem. (1987) [Pubmed]
  22. Imbalance between cysteine proteases and inhibitors in a baboon model of bronchopulmonary dysplasia. Altiok, O., Yasumatsu, R., Bingol-Karakoc, G., Riese, R.J., Stahlman, M.T., Dwyer, W., Pierce, R.A., Bromme, D., Weber, E., Cataltepe, S. Am. J. Respir. Crit. Care Med. (2006) [Pubmed]
  23. Interaction of human stefin B in the prefibrillar oligomeric form with membranes. Correlation with cellular toxicity. Anderluh, G., Gutierrez-Aguirre, I., Rabzelj, S., Ceru, S., Kopitar-Jerala, N., Macek, P., Turk, V., Zerovnik, E. FEBS J. (2005) [Pubmed]
  24. Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy. Lalioti, M.D., Scott, H.S., Buresi, C., Rossier, C., Bottani, A., Morris, M.A., Malafosse, A., Antonarakis, S.E. Nature (1997) [Pubmed]
  25. Role of the single cysteine residue, Cys 3, of human and bovine cystatin B (stefin B) in the inhibition of cysteine proteinases. Pol, E., Björk, I. Protein Sci. (2001) [Pubmed]
  26. Reduced serotonin and 3-hydroxyanthranilic acid levels in serum of cystatin B-deficient mice, a model system for progressive myoclonus epilepsy. Arbatova, J., D'Amato, E., Vaarmann, A., Zharkovsky, A., Reeben, M. Epilepsia (2005) [Pubmed]
  27. Solution structure of a human cystatin A variant, cystatin A2-98 M65L, by NMR spectroscopy. A possible role of the interactions between the N- and C-termini to maintain the inhibitory active form of cystatin A. Tate, S., Ushioda, T., Utsunomiya-Tate, N., Shibuya, K., Ohyama, Y., Nakano, Y., Kaji, H., Inagaki, F., Samejima, T., Kainosho, M. Biochemistry (1995) [Pubmed]
  28. Elongation on the amino-terminal part of stefin B decreases inhibition of cathepsin H. Jerala, R., Kroon-Zitko, L., Popovic, T., Turk, V. Eur. J. Biochem. (1994) [Pubmed]
  29. Degradation of laminin by human tumor cathepsin B. Lah, T.T., Buck, M.R., Honn, K.V., Crissman, J.D., Rao, N.C., Liotta, L.A., Sloane, B.F. Clin. Exp. Metastasis (1989) [Pubmed]
  30. Localization of the EPM1 gene for progressive myoclonus epilepsy on chromosome 21: linkage disequilibrium allows high resolution mapping. Lehesjoki, A.E., Koskiniemi, M., Norio, R., Tirrito, S., Sistonen, P., Lander, E., de la Chapelle, A. Hum. Mol. Genet. (1993) [Pubmed]
  31. Isolation and characterization of the mouse cystatin B gene. Pennacchio, L.A., Myers, R.M. Genome Res. (1996) [Pubmed]
  32. Cathepsin D inactivates cysteine proteinase inhibitors, cystatins. Lenarcic, B., Kos, J., Dolenc, I., Lucovnik, P., Krizaj, I., Turk, V. Biochem. Biophys. Res. Commun. (1988) [Pubmed]
  33. Stefin B, the major low molecular weight inhibitor in ovarian carcinoma. Kastelic, L., Turk, B., Kopitar-Jerala, N., Stolfa, A., Rainer, S., Turk, V., Lah, T.T. Cancer Lett. (1994) [Pubmed]
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