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CSTB
cystatin B
CSTB encodes cystatin B, a protein that regulates enzyme activity in cells and protects nerve cells from damage. The CSTB gene provides instructions for making cystatin B, a small regulatory protein that controls the activity of protein-degrading enzymes called cathepsins.
CSTB is located on the long (q) arm of chromosome 21, at band 21q22.3. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 21 in the library →Overview
The CSTB gene, located on chromosome 21, encodes a protein called cystatin B (also known as stefin B). At just 98 amino acids in length, this molecule is a member of the protease inhibitor family and works to regulate cathepsin enzyme function inside cells [PMID:10942430]. Cystatin B is particularly important in the nervous system, where it supports neuronal development, cell-to-cell communication, and protection against oxidative damage.
Pathogenic changes in CSTB are associated with Unverricht-Lundborg disease, a progressive myoclonic epilepsy characterised by muscle jerks, seizures, and gradual neurological decline. The condition follows an autosomal recessive inheritance pattern, meaning two altered copies of the gene must be present for the disease to develop.
What the gene does
Cystatin B works by limiting the activity of cathepsin enzymes, which break down specific proteins within cellular structures known as lysosomes [PMID:8528245]. Lysosomes act as the cell's recycling system, processing molecules that are no longer required. When cathepsins escape from lysosomes into other cellular compartments, cystatin B helps shield important proteins from unwanted degradation.
Within the nervous system, cystatin B appears to fulfil additional protective functions. Research suggests the protein helps modulate inflammatory responses and guards neurons against oxidative stress, a condition where reactive molecules accumulate and threaten cellular integrity [PMID:11823364]. Evidence also indicates that cystatin B supports the proper development, migration, and signalling of nerve cells, though scientists continue to investigate the exact mechanisms. The protein's activity seems especially important when neurons are highly active and face greater metabolic challenges.
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Chromosome location
The CSTB gene is located on the long arm of chromosome 21 at position 22.3, designated as 21q22.3. This chromosomal region contains several genes involved in neurological function. A distinctive feature of CSTB is the presence of a dodecamer repeat sequence in the regulatory region that controls gene activity. This 12-nucleotide sequence normally repeats two or three times in the general population. The gene's position on chromosome 21 means that individuals with Down syndrome, who have three copies of this chromosome, produce elevated levels of cystatin B protein.
Protein structure
Cystatin B is a compact protein comprising 98 amino acids. The protein contains a secondary area of contact motif spanning amino acids 46-50, which contributes to its interaction with target cathepsin enzymes. As a member of the stefin subfamily of cystatins, this protein lacks the signal peptide and disulphide bonds present in some other cystatin family members, allowing it to function within the cell cytoplasm rather than being secreted. The protein's relatively small size and stable structure enable it to act as an effective competitive inhibitor of cathepsins, binding to these enzymes and preventing them from degrading cellular proteins.
Key variants
The majority of pathogenic variants in CSTB involve expansions of the dodecamer repeat in the gene's regulatory region. While the normal gene contains two or three copies of this 12-nucleotide sequence, affected individuals typically carry substantially larger expansions. These expansions reduce the amount of cystatin B protein produced by the cell. Less commonly, some individuals carry variants that result in complete loss of protein production, which generally leads to more severe manifestations. The variant spectrum reflects the gene's regulatory architecture, with most pathogenic changes affecting gene expression rather than altering the protein's amino acid sequence.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.136C>T | p.Gln46Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.145del | p.Ala49fs | Pathogenic | ★★☆☆ | Progressive myoclonic epilepsy |
c.202C>T | p.Arg68Ter | Pathogenic | ★★☆☆ | CSTB-related disorder |
c.218_219del | p.Leu73fs | Pathogenic/Likely pathogenic | ★★☆☆ | CSTB-related disorder |
c.64C>T | p.Gln22Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Progressive myoclonic epilepsy |
c.67-1G>C | - | Pathogenic | ★★☆☆ | Cerebral dysmyelination |
g.(?_45194083)_(45196150_?)del | - | Pathogenic | ★☆☆☆ | Progressive myoclonic epilepsy |
c.121del | p.Val41fs | Pathogenic | ★☆☆☆ | Progressive myoclonic epilepsy |
c.200_203dup | p.Val69fs | Pathogenic | ★☆☆☆ | Progressive myoclonic epilepsy |
c.67-1G>A | - | Pathogenic | ★☆☆☆ | Progressive myoclonic epilepsy |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in CSTB cause Unverricht-Lundborg disease (also known as EPM1 or progressive myoclonic epilepsy type 1), a rare neurological condition that typically begins in childhood or adolescence. The condition is characterised by stimulus-sensitive myoclonic jerks (sudden, brief muscle contractions), generalised tonic-clonic seizures, and gradual loss of coordination and balance. Cognitive function may decline slowly over time, though intellectual disability is not a primary feature at onset. In rare cases where no functional cystatin B is produced, individuals may present with more severe features including microcephaly, significant developmental delays, abnormal movements, and seizures. The condition follows an autosomal recessive inheritance pattern.
Inheritance pattern
Conditions caused by pathogenic CSTB variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
CSTB is included in multiple NHS Genomic Medicine Service gene panels focused on neurological conditions. The gene appears on panels for early onset or syndromic epilepsy, hereditary ataxia, childhood onset dystonia and related movement disorders, and intellectual disability. It is also listed in the Developmental Disorders Genotype-Phenotype (DDG2P) database, which catalogues genes associated with developmental conditions. This broad panel membership reflects the range of neurological manifestations associated with CSTB variants and ensures that appropriate testing is available through NHS pathways for individuals with relevant clinical presentations.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the dodecamer repeat expansion in CSTB?
The dodecamer repeat is a 12-nucleotide DNA sequence in the regulatory region of CSTB that normally appears two or three times. In most people with Unverricht-Lundborg disease, this sequence is abnormally expanded, which reduces the amount of cystatin B protein the cell can produce.
How is Unverricht-Lundborg disease inherited?
Unverricht-Lundborg disease follows an autosomal recessive inheritance pattern. This means an individual must inherit two altered copies of the CSTB gene, one from each parent, to develop the condition. Parents who each carry one altered copy typically do not show symptoms.
Why is cystatin B particularly important in nerve cells?
Nerve cells appear especially vulnerable to reduced cystatin B function, possibly because they have high metabolic activity and generate more cellular waste that must be managed by lysosomes. Cystatin B helps protect neurons from cathepsin enzymes that might leak from lysosomes, and also appears to regulate inflammation and oxidative stress responses in the nervous system.
References
- Joensuu T, Kuronen M, Alakurtti K. Cystatin B: mutation detection, alternative splicing and expression in progressive myclonus epilepsy of Unverricht-Lundborg type (EPM1) patients. European journal of human genetics : EJHG. 2007. PMID: 17003839
- Alakurtti K, Weber E, Rinne R. Loss of lysosomal association of cystatin B proteins representing progressive myoclonus epilepsy, EPM1, mutations. European journal of human genetics : EJHG. 2005. PMID: 15483648
- Shahwan A, Farrell M, Delanty N. Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. The Lancet. Neurology. 2005. PMID: 15778103
- Ceru S, Rabzelj S, Kopitar-Jerala N. Protein aggregation as a possible cause for pathology in a subset of familial Unverricht-Lundborg disease. Medical hypotheses. 2005. PMID: 15780491
- Lehesjoki AE. Molecular background of progressive myoclonus epilepsy. The EMBO journal. 2003. PMID: 12853462
- Houseweart MK, Pennacchio LA, Vilaythong A. Cathepsin B but not cathepsins L or S contributes to the pathogenesis of Unverricht-Lundborg progressive myoclonus epilepsy (EPM1). Journal of neurobiology. 2003. PMID: 12918016
- Moulard B, Darcel F, Mignard D. FOunder effect in patients with Unverricht-Lundborg disease on reunion island. Epilepsia. 2003. PMID: 14510831
- Lalioti MD, Antonarakis SE, Scott HS. The epilepsy, the protease inhibitor and the dodecamer: progressive myoclonus epilepsy, cystatin b and a 12-mer repeat expansion. Cytogenetic and genome research. 2003. PMID: 14526183
- Moulard B, Genton P, Grid D. Haplotype study of West European and North African Unverricht-Lundborg chromosomes: evidence for a few founder mutations. Human genetics. 2002. PMID: 12215838
- Alakurtti K, Virtaneva K, Joensuu T. Characterization of the cystatin B gene promoter harboring the dodecamer repeat expanded in progressive myoclonus epilepsy, EPM1. Gene. 2000. PMID: 10721698