Disease relevance of CSTB

• Cystatin B is an anti-protease implicated in myoclonus epilepsy, a degenerative disease of the central nervous system [1].
• Progressive myoclonus epilepsy (EPM1) is an autosomal recessive disorder, characterized by severe, stimulus-sensitive myoclonus and tonic-clonic seizures [2].
• Cysteine proteinase inhibitors stefin A, stefin B, and cystatin C in sera from patients with colorectal cancer: relation to prognosis [3].
• Cloning a synthetic gene for human stefin B and its expression in E. coli [4].
• The decrease in median cytoplasmic staining of cystatin B in carcinomas compared to other lesions was significant, but there was a significant increase in expression with dedifferentiation of carcinoma [5].
• The serum CSTB level was much higher in HCC patients than in those with nonmalignant chronic liver disease (groups 2 and 3; P < 0.0001) [6].

Psychiatry related information on CSTB

• Amyloid beta (A beta) protein is the key component of amyloid plaques in Alzheimer's disease brain whereas stefin B is an intracellular cysteine proteinase inhibitor, broadly distributed in different tissue and recently reported to form amyloid fibrils in vitro [7].

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

• None of the PME derivatives in the pyrimidine series, their 6-aza or 3-deaza analogues, exhibited any activity against DNA viruses or retroviruses tested, except for the 5-bromocytosine derivative [11].
• During a muscle contracture, induced by acute muscle stimulation, PFK-deficient muscle became completely depleted of PCr and ATP, accumulated large amounts of PME, and recovered very slowly [12].
• Five patients, four with EPM 1 (Unverricht-Lundborg disease) and one patient with EPM2 (Lafora body disease) were treated with 6 g/day of NAC [13].
• Eleven patients with long-standing progressive myoclonus epilepsy, PME, and age- and sex-matched epileptic controls received L-tryptophan (L-Trp) 100 mg/kg body weight combined with carbidopa in addition to their usual anticonvulsant regimen [14].
• Clofibrate (CPIB), an antihyperlipidemic agent, was employed as a drug response modulator in this study to evaluate its action, if any, on adriamycin (ADR) cytotoxicity in adriamycin insensitive chronic myeloid leukemia (CML) cells in vitro [15].

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

• Staining of cathepsin B, D, H, L, stefin B and cystatin C was observed in the cytoplasm of epithelial cells in decidua [20].
• In the malignant keratinocytes cystatin B follows the behaviour of cystatin A [21].
• In addition, cathepsin H and cystatin B were colocalized in type 2 alveolar epithelial cells [22].
• Interaction of granular aggregates and globular oligomers of an amyloidogenic protein, human stefin B, with model lipid membranes and monolayers was studied [23].
• Normal alleles contain 2 or 3 copies of this repeat whereas mutant alleles contain more than 60 such repeats and have reduced levels of CSTB messenger RNA in blood but not in cell lines. 'Premutation' CSTB alleles with 12-17 repeats show marked instability when transmitted to offspring [24].

Associations of CSTB with chemical compounds

• CONCLUSIONS: This is the first demonstration of cysteine protease activity being regulated by CSTB activity in a biological context [19].
• The Cys-to-Ser mutation resulted in weaker binding of cystatin B to all four proteinases examined, the effect varying with both the proteinase and the species variant of the inhibitor [25].
• A gene coding for human stefin B was synthesized by the solid-phase phosphite method and cloned in the pUC8 cloning vector [4].
• In addition, they show stronger interaction with 1,2-dioleoyl-sn-glycero-3-phosphocholine and 1,2-dioleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] monolayers than native stefin A or nonaggregated stefin B [23].
• RESULTS: Reduced levels of 5-HT and KYN intermediate metabolite 3-hydroxyanthranilic acid were found in serum of CSTB-deficient mice [26].

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

• Reduced cystatin B activity correlates with enhanced cathepsin activity in progressive myoclonus epilepsy [19].
• The proteolysis of laminin by tumor cathepsin B could be inhibited by an active site titrant for cysteine proteinases or stefin B, an endogenous low-Mr cysteine proteinase inhibitor [29].

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].

References