Atlas of Genetics and Cytogenetics in Oncology and Haematology

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CSTB (cystatin B (stefin B))

Written2008-07Zala Jevnikar, Janko Kos
Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia

(Note : for Links provided by Atlas : click)


HGNC Alias symbCST6
HGNC Alias namestefin B
 Epilepsy, progressive myoclonic 1
HGNC Previous nameEPM1
HGNC Previous namecystatin B (stefin B)
LocusID (NCBI) 1476
Atlas_Id 40181
Location 21q22.3  [Link to chromosome band 21q22]
Location_base_pair Starts at 43773950 and ends at 43776308 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping CSTB.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CACYBP (1q25.1)::CSTB (21q22.3)CALU (7q32.1)::CSTB (21q22.3)CSTB (21q22.3)::CSTB (21q22.3)
CSTB (21q22.3)::ERGIC1 (5q35.1)CSTB (21q22.3)::EXT2 (11p11.2)CSTB (21q22.3)::TMEM147 (19q13.12)
IL4I1 (19q13.33)::CSTB (21q22.3)


Description The stefin B gene is located on human chromosome 21q22.3 and it contains 3 exons and 2 introns. The transcript length of stefin B mRNA is 294 bps. A novel variant, with retention of the entire intron 2 is transcribed from two exons with an ORF of 249 bp. It encodes a putative 9.0-kDa protein of 83 amino acids, including 57 identical to stefin B followed by 26 amino acids encoded by the intron 2 sequences.


  Richardson diagram of stefin B structure: alpha-helixes are shown in red and beta-sheets in green (MEROPS: the peptidase database - I25.003: cystatin B).
Description The cystatin superfamily comprises at least four families of closely related proteins, such as stefins (family I), cystatins (family II), kininogens (family III), and various structurally related but noninhibitory proteins of family IV. A significant structural difference between stefins and cystatins is the signal peptide, which is responsible for extracellular targeting of cystatins, whereas stefins lack this peptide and have been reported as intracellular inhibitors. Human stefin B is a single chain protein consisting of 98 amino acid residues, with a molecular mass of 11,175 kDa. Stefin B is a neutral protein with pI values between 5.9 - 6.5 and is able to form a dimmer stabilized by noncovalent forces. Like other members of the cystatin superfamily, stefin B is reversible and competitive inhibitor of cysteine proteases, particularly cathepsin L and cathepsin S with Ki values in the picomolar range whereas cathepsin B inhibition is weaker (Ki 10-7M).
Expression Stefin B is widely distributed among different cell types and tissues. Although it lacks an export signal sequence and is generally thought to function intracellularly, it has also been found in extracellular fluid.
Function Stefin B is thought to play a role in protecting cytosolic and cytoskeleton proteins against the cysteine proteases accidentally released from lysosomes. Besides protease inactivation stefin B could bind other proteins in a multiprotein complex which might contribute to the disease in patients with progressive myoclonus epilepsy. Decreased levels of stefin B mRNA were detected in patients with progressive myoclonus epilepsy and associated with excessive activity of cathepsin B. Moreover, stefin B may be important in the control of osteoclasts bone resorption. It inhibits bone resorption by down-regulating intracellular cathepsin K activity. On the other hand stefin B protected osteoclasts from experimentally induced apoptosis, promoting cell survival in the nervous system.
Homology Human stefin B exhibit a high degree of homology to other cysteine protease inhibitors of the cystatin superfamily which includes human stefin A and the homologues in other species. It is 79% identical with cystatin beta from rat liver, but contains only a single cysteine.


Note Eight mutations in the stefin B gene have been reported to associate with an autosomal recessive neurodegenerative disorder, progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1). Most of the disease alleles harbour an unstable expansion of at least 30 copies of a normally polymorphic 12-nucleotide, dodecamer repeat located in the promoter region of the stefin B gene. Three reported EPM1 mutations affect splice sites, two result in amino-acid changes and two predict truncated proteins either through creating a stop codon or producing a frameshift.

Implicated in

Entity Invasive cancers
Disease Higher levels of stefin B in tumours have been determined in lung, breast, head and neck and prostate cancer as well as in murine lymphosarcomas, hepatomas and Lewis lung carcinomas. These higher levels, up to a certain level, may counter-balance the excessive activity of cysteine cathepsins, associated with matrix remodelling resulting in the progression of the disease. On the other hand, high cytosolic levels of stefins may be relevant for regulation of apoptosis, when initiated via lysosomal cell death pathway inhibiting cathepsin B, which was proposed as a dominant execution protease in the lysosomal apoptotic pathways, induced in a variety of tumour cells by tumour necrosis factor alpha ( TNF-alpha ). In some studies lower levels of stefins in tumours have been reported. Lower mRNA levels of stefin B have been reported in breast and esophagus tumours as compared to adjacent control tissues.
Although stefins are cytosolic proteins, they have also been detected in body fluids of cancer patients. Stefin B has been detected in ascitic fluid from patients with ovarian carcinoma and in bronhoalveolar fluid of lung cancer patients.
Diagnosis: The poor survival rate of hepatocellular carcinoma is in part due to the inability to diagnose patients at an early stage. Stefin B is specifically overexpressed in most hepatocellular carcinoma and is also elevated in the serum of a large proportion of hepatocellular carcinoma patients. Stefin B may be a useful marker for diagnosing patients with hepatocellular carcinoma with a high sensitivity.
Prognosis Higher levels of stefin B in tumour tissues have been shown to correlate with a favourable prognosis of cancer patients. A significant prognostic value of stefin B was determined in patients with lung and head and neck cancer. On the other hand, animal model with excluded expression of stefin B did not support its suppressive function in cancer. A significantly lower metastatic spread was detected in stefin B knock-out mice than in wild-type animals. Similarly, higher levels of stefin B in body fluids have been associated with a poor prognosis of cancer patients. Alterations in secretion may result in higher extracellular and lower intracellular levels of stefins and, therefore, a reverse correlation with patient' survival is to be expected.
Oncogenesis Increased levels of cysteine protease activity, not being balanced by a corresponding increase of cysteine protease inhibitors are associated with progression of malignant disease and poor patient's prognosis. Enhanced expression of stefin B would be expected to diminish the tumour-associated proteolytic activity and indeed, there is evidence of a suppressive role of stefin B in various cancer types.
Entity Progressive myoclonus epilepsy
Disease The progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is an autosomal recessive disease characterized by progressive myoclonic jerks and decline in cognition. Genetic linkage studies, suggest the involvement of the stefin B gene. A decreased amount of stefin B mRNA is a common finding in EPM1 patients and it may be due to: 1) a mutation in the promoter region causing a decrease in the rate of transcription of the gene or 2) mutations of the coding region/splice sites that may inhibit translation or diminish the half-life of the transcript and/or of the protein. The availability of a stefin B knock-out mouse as a model for the disease has allowed identification of the presence of severe apoptotic damage to the cerebellar granule cells. This observation combined with the anti-protease function of stefin B protein has suggested that it may have an anti-apoptotic function in the cerebellum. It was shown that a number of proteins (manly proteins that are involved in the regulation of cytoskeletal functions) that are not proteases can interact specifically with stefin B, forming a multiprotein complex. The first hypothesis is that stefin B may be active as antiprotease, protecting the complex against the attack of proteases. An alternative hypothesis is that stefin B may bind to the interacting proteins modifying the structure, thus allowing the correct formation of the complex. A further hypothesis is the sequestration of stefin B by the multiprotein complex, thus impeding its interaction with cathepsins.


Friends and relations of the cystatin superfamily--new members and their evolution.
Brown WM, Dziegielewska KM.
Protein Sci. 1997 Jan;6(1):5-12.
PMID 9007972
Cystatin B and its EPM1 mutants are polymeric and aggregate prone in vivo.
Cipollini E, Riccio M, Di Giaimo R, Dal Piaz F, Pulice G, Catania S, Caldarelli I, Dembic M, Santi S, Melli M.
Biochim Biophys Acta. 2008 Feb;1783(2):312-22. Epub 2007 Sep 4.
PMID 17920138
Cystatin B: mutation detection, alternative splicing and expression in progressive myclonus epilepsy of Unverricht-Lundborg type (EPM1) patients.
Joensuu T, Kuronen M, Alakurtti K, Tegelberg S, Hakala P, Aalto A, Huopaniemi L, Aula N, Michellucci R, Eriksson K, Lehesjoki AE.
Eur J Hum Genet. 2007 Feb;15(2):185-93. Epub 2006 Sep 27.
PMID 17003839
Towards novel anti-cancer strategies based on cystatin function.
Keppler D.
Cancer Lett. 2006 Apr 28;235(2):159-76.
PMID 15893421
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 HJ, Christensen IJ, Brunner N.
Clin Cancer Res. 2000 Feb;6(2):505-11.
PMID 10690531
Cysteine proteinases and their endogenous inhibitors: target proteins for prognosis, diagnosis and therapy in cancer (review).
Kos J, Lah TT.
Oncol Rep. 1998 Nov-Dec;5(6):1349-61.
PMID 9769367
Identification of cystatin B as a potential serum marker in hepatocellular carcinoma.
Lee MJ, Yu GR, Park SH, Cho BH, Ahn JS, Park HJ, Song EY, Kim DG.
Clin Cancer Res. 2008 Feb 15;14(4):1080-9.
PMID 18281540
Isolation and characterization of the mouse cystatin B gene.
Pennacchio LA, Myers RM.
Genome Res. 1996 Nov;6(11):1103-9.
PMID 8938434
Amino acid sequence of the intracellular cysteine proteinase inhibitor cystatin B from human liver.
Ritonja A, Machleidt W, Barrett AJ.
Biochem Biophys Res Commun. 1985 Sep 30;131(3):1187-92.
PMID 3902020
Cysteine cathepsins (proteases)--on the main stage of cancer?
Turk V, Kos J, Turk B.
Cancer Cell. 2004 May;5(5):409-10.
PMID 15144947


This paper should be referenced as such :
Jevnikar, Z ; Kos, J
CSTB (cystatin B (stefin B))
Atlas Genet Cytogenet Oncol Haematol. 2009;13(6):406-408.
Free journal version : [ pdf ]   [ DOI ]

External links


HGNC (Hugo)CSTB   2482
LRG (Locus Reference Genomic)LRG_485
Atlas Explorer : (Salamanque)CSTB
Entrez_Gene (NCBI)CSTB    cystatin B
AliasesCPI-B; CST6; EPM1; EPM1A; 
GeneCards (Weizmann)CSTB
Ensembl hg19 (Hinxton)ENSG00000160213 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000160213 [Gene_View]  ENSG00000160213 [Sequence]  chr21:43773950-43776308 [Contig_View]  CSTB [Vega]
ICGC DataPortalENSG00000160213
Genatlas (Paris)CSTB
SOURCE (Princeton)CSTB
Genetics Home Reference (NIH)CSTB
Genomic and cartography
GoldenPath hg38 (UCSC)CSTB  -     chr21:43773950-43776308 -  21q22.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CSTB  -     21q22.3   [Description]    (hg19-Feb_2009)
GoldenPathCSTB - 21q22.3 [CytoView hg19]  CSTB - 21q22.3 [CytoView hg38]
Genome Data Viewer NCBICSTB [Mapview hg19]  
OMIM254800   601145   
Gene and transcription
Genbank (Entrez)AK312133 BC003370 BC010532 BT007040 BX419549
RefSeq transcript (Entrez)NM_000100
Consensus coding sequences : CCDS (NCBI)CSTB
Gene ExpressionCSTB [ NCBI-GEO ]   CSTB [ EBI - ARRAY_EXPRESS ]   CSTB [ SEEK ]   CSTB [ MEM ]
Gene Expression Viewer (FireBrowse)CSTB [ Firebrowse - Broad ]
GenevisibleExpression of CSTB in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)1476
GTEX Portal (Tissue expression)CSTB
Human Protein AtlasENSG00000160213-CSTB [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP04080   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP04080  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP04080
Domaine pattern : Prosite (Expaxy)CYSTATIN (PS00287)   
Domains : Interpro (EBI)Cystatin_dom    Prot_inh_cystat_CS    Prot_inh_stefin   
Domain families : Pfam (Sanger)Cystatin (PF00031)   
Domain families : Pfam (NCBI)pfam00031   
Domain families : Smart (EMBL)CY (SM00043)  
Conserved Domain (NCBI)CSTB
PDB (RSDB)1STF    2OCT    4N6V   
PDB Europe1STF    2OCT    4N6V   
PDB (PDBSum)1STF    2OCT    4N6V   
PDB (IMB)1STF    2OCT    4N6V   
Structural Biology KnowledgeBase1STF    2OCT    4N6V   
SCOP (Structural Classification of Proteins)1STF    2OCT    4N6V   
CATH (Classification of proteins structures)1STF    2OCT    4N6V   
AlphaFold pdb e-kbP04080   
Human Protein Atlas [tissue]ENSG00000160213-CSTB [tissue]
Protein Interaction databases
IntAct (EBI)P04080
Ontologies - Pathways
Ontology : AmiGOprotease binding  protease binding  RNA binding  endopeptidase inhibitor activity  cysteine-type endopeptidase inhibitor activity  cysteine-type endopeptidase inhibitor activity  extracellular region  extracellular space  extracellular space  nucleus  nucleolus  cytoplasm  cytosol  cytosol  adult locomotory behavior  negative regulation of peptidase activity  negative regulation of endopeptidase activity  secretory granule lumen  negative regulation of proteolysis  collagen-containing extracellular matrix  extracellular exosome  tertiary granule lumen  ficolin-1-rich granule lumen  
Ontology : EGO-EBIprotease binding  protease binding  RNA binding  endopeptidase inhibitor activity  cysteine-type endopeptidase inhibitor activity  cysteine-type endopeptidase inhibitor activity  extracellular region  extracellular space  extracellular space  nucleus  nucleolus  cytoplasm  cytosol  cytosol  adult locomotory behavior  negative regulation of peptidase activity  negative regulation of endopeptidase activity  secretory granule lumen  negative regulation of proteolysis  collagen-containing extracellular matrix  extracellular exosome  tertiary granule lumen  ficolin-1-rich granule lumen  
REACTOMEP04080 [protein]
REACTOME PathwaysR-HSA-6798695 [pathway]   
NDEx NetworkCSTB
Atlas of Cancer Signalling NetworkCSTB
Wikipedia pathwaysCSTB
Orthology - Evolution
GeneTree (enSembl)ENSG00000160213
Phylogenetic Trees/Animal Genes : TreeFamCSTB
Homologs : HomoloGeneCSTB
Homology/Alignments : Family Browser (UCSC)CSTB
Gene fusions - Rearrangements
Fusion Cancer (Beijing)CACYBP [1q25.1]  -  CSTB [21q22.3]  [FUSC000965]
Fusion : QuiverCSTB
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCSTB [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CSTB
Exome Variant ServerCSTB
GNOMAD BrowserENSG00000160213
Varsome BrowserCSTB
ACMGCSTB variants
Genomic Variants (DGV)CSTB [DGVbeta]
DECIPHERCSTB [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCSTB 
ICGC Data PortalCSTB 
TCGA Data PortalCSTB 
Broad Tumor PortalCSTB
OASIS PortalCSTB [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICCSTB  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DCSTB
Mutations and Diseases : HGMDCSTB
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)CSTB
DoCM (Curated mutations)CSTB
CIViC (Clinical Interpretations of Variants in Cancer)CSTB
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
OMIM254800    601145   
Orphanet294    7026   
Genetic Testing Registry CSTB
NextProtP04080 [Medical]
Target ValidationCSTB
Huge Navigator CSTB [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDCSTB
Pharm GKB GenePA26984
Clinical trialCSTB
DataMed IndexCSTB
PubMed126 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Thu Jan 20 14:04:56 CET 2022

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