Alternative titles; symbols
HGNC Approved Gene Symbol: CST3
SNOMEDCT: 45639009;
Cytogenetic location: 20p11.21 Genomic coordinates (GRCh38): 20:23,626,706-23,637,955 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p11.21 | {Macular degeneration, age-related, 11} | 611953 | 3 | |
| Cerebral amyloid angiopathy | 105150 | Autosomal dominant | 3 |
Cystatin C, which belongs to the type II cystatin gene family, is a potent inhibitor of lysosomal proteinases (Pirttila et al., 2005).
Grubb and Lofberg (1982) reported the amino acid sequence of cystatin C, which they referred to as 'gamma-trace,' isolated from human urine. It is a single 120-residue polypeptide with a molecular mass of approximately 13.26 kD. The protein is constitutively secreted shortly after synthesis (Barrett et al., 1984; Merz et al., 1997).
Abrahamson et al. (1987) isolated recombinant cystatin C-producing clones from a human placenta lambda-gt11 cDNA library. One of the clones encoded a 120-amino acid complete mature cystatin C protein with a 26-residue hydrophobic leader sequence, suggesting an extracellular function. The deduced protein sequence confirmed the protein sequence of cystatin C isolated from human urine.
Abrahamson (1988) reported the isolation and characterization of 6 human cysteine proteinase inhibitors, including cystatin C. Whereas cystatins D (123858), S (123857), and SA (123856) are expressed primarily in salivary glands, cystatin C is expressed in virtually all organs of the body. According to its high concentration in biologic fluids, the authors concluded that cystatin C is probably one of the most important extracellular inhibitors of cysteine proteases.
Abrahamson et al. (1990) determined that the CST3 gene contains 3 exons and spans 4.3 kb.
Huh et al. (1995) determined the structure of the mouse Cst3 gene by sequencing a 6.1-kb genomic DNA containing the entire gene, as well as 0.9 kb of the 5-prime flanking region and 1.7 kb of the 3-prime flanking region. The sequence revealed an overall organization very similar to that of the human CST3 gene.
By human-rodent somatic cell hybridizations, Abrahamson et al. (1989) mapped the human CST3 to chromosome 20.
Using Southern blot analysis, pulsed field gel electrophoresis (PFGE), and both radioactive and fluorescence in situ hybridization, Rao et al. (1991) confirmed the assignment of CST3 and the other family II cystatins to chromosome 20. PFGE with a cystatin-C-specific probe showed a single 300-kb BssHII fragment and in situ hybridization mapped the locus specifically to 20p11. This location was found to be proximal to the breakpoint in a patient with Alagille syndrome (see 118450).
From the results of fluorescence in situ hybridization, Southern blot, and PFGE studies, Schnittger et al. (1993) concluded that CST3 and probably 7 other members of the cystatin gene family are clustered within a 1.2-Mb segment on chromosome 20p11.2. By fluorescence in situ hybridization, Dickinson et al. (1994) showed that the cystatin gene cluster (CST1 to 5, CST1 and 2 pseudogenes) spans less than 905 kb.
Huh et al. (1995) mapped the mouse Cst3 gene to distal mouse chromosome 2.
Cystatin C, which was first referred to as 'gamma-trace,' was originally described as a constituent of normal cerebrospinal fluid (CSF) and of urine from patients with renal failure (Grubb and Lofberg, 1982). It is present in a number of neuroendocrine cells and its concentration in the CSF was reported to be 5.5 times that in plasma of healthy adults (Lofberg and Grubb, 1979; Lofberg et al., 1981; Lofberg et al., 1983). Grubb and Lofberg (1982) detected the protein in human pituitary gland, and suggested that it is part of the gastroenteropancreatic neuroendocrine system.
The pathogenesis of atherosclerosis and abdominal aortic aneurysm (AAA; 100070) involves breakdown of the elastic laminae. Elastolytic cysteine proteases, including cathepsins S (CTSS; 116845) and K (CTSK; 601105), are overexpressed at sites of arterial elastin damage. In both atherosclerotic and aneurysmal aortic lesions, Shi et al. (1999) found a severe reduction in cystatin C levels compared to normal vascular wall smooth muscle cells. Among 122 AAA patients screened by ultrasonography, increased abdominal aortic diameter correlated inversely with serum cystatin C levels. In vitro, cytokine-stimulated vascular smooth muscle cells secreted cathepsins whose elastolytic activity could be blocked when cystatin C secretion was induced by treatment with TGF-beta-1 (190180). These findings highlighted a potentially important role for imbalance between cysteine proteases and cystatin C in arterial wall remodeling and established that cystatin C deficiency occurs in vascular disease. Shi et al. (1999) stated that the marked suppression of cystatin C concurrent with augmented expression of cysteine proteases observed in their studies represented the first acquired cysteine protease inhibitor deficiency in human disease.
Pirttila et al. (2005) found increased cystatin C expression in the glial cells in the molecular layer of the hippocampal dentate gyrus in brain tissue from 61 patients with temporal lobe epilepsy (see, e.g., 608096) who underwent epilepsy surgery. The findings were most pronounced in 26 patients with hippocampal sclerosis and in those with granule cell dispersion. High cystatin C expression was also associated with abnormal migration of newborn neuronal cells. Similar findings were observed in rat models of chronic epilepsy. Pirttila et al. (2005) concluded that cystatin C is involved in network reorganization in the epileptic dentate gyrus.
In CSF samples from 19 of 29 patients with multiple sclerosis (MS; 126200), Irani et al. (2006) identified a 12.5-kD cleavage product of cystatin C formed by the removal of the last 8 amino acids from the C terminus. The 12.5-kD peak was not identified in CSF samples from 27 patients with unrelated neurologic disorders or 27 additional patients with acute transverse myelitis, but lower levels than that of MS patients were found in some patients with HIV infection. Irani et al. (2006) suggested that cleavage of cystatin C may be an adaptive host response.
Del Boccio et al. (2007) and Hansson et al. (2007) independently identified a 12.5-kD product of cystatin C that is formed by degradation of the first 8 N-terminal amino acids resulting from inappropriate storage at -20 degrees Celsius. Compared to controls, no significant differences in cystatin C fragments were observed in the CSF of 21 and 43 MS patients, respectively. Both groups concluded that CSF cystatin C is not a useful marker for the diagnosis of MS. In a response, Wheeler et al. (2007) stated that they had stored the CSF samples at -80 degrees Celsius (Irani et al., 2006), and that the cleavage site identified by them was at the C-terminal. A more accurate measurement indicated that the C-terminal fragment was 12,546.6 Da and the N-terminal fragment was 12,561.3 Da, suggesting that there are 2 similarly sized, yet distinct fragments of cystatin C.
Balbin and Abrahamson (1991) identified 3 variants within an 85-bp segment in the promoter region of the CST3 gene. All 3 were on the same allele and displayed mendelian inheritance. The polymorphisms were apparently linked, since alleles carrying only 1 of the 3 base changes were not identified. The variant allele, termed 'B,' had a frequency of 0.29 ('A' had a frequency of 0.71). The 3 polymorphisms result in 2 commonly found haplotypes: 'A,' comprising -157G, -72A, and +73G, and 'B,' comprising -157C, -72C, and +73A (Olafsson, 1995; Finckh et al., 2000).
Cerebroarterial Amyloidosis, Icelandic Type
Using high performance liquid chromatography (HPLC) tryptic fingerprint analyses, Ghiso et al. (1986) found differences between normal cystatin C and a cystatin C variant in Icelandic amyloidosis (105150), which is also known as hereditary cerebral hemorrhage with amyloidosis (HCHWA). In a patient with HCHWA, Abrahamson et al. (1987) identified a mutation in the CST3 gene (L68Q; 604312.0001). Jensson et al. (1987) found abnormal cystatin C protein sequences in the amyloid protein deposited in patients with Icelandic-type amyloidosis. Abnormalities included absence of 10 amino acids from the amino terminal and an amino acid substitution at position 58, which corresponded to position 68 in cystatin C.
Alzheimer Disease
By linkage analysis, Blacker et al. (1997) and Goddard et al. (2004) identified a susceptibility locus for late-onset Alzheimer disease (AD8; 607116) in an 11.8-cM candidate region on chromosome 20 containing the CST3 gene. Goddard et al. (2004) observed an association between AD and markers located near the CST3 gene.
Among 517 AD patients, Finckh et al. (2000) found that homozygosity for the CST3 B haplotype was significantly associated with late-onset AD (odds ratio of 3.8). Crawford et al. (2000) found an association between the +73G allele and late-onset AD. However, Monastero et al. (2005) and Nacmias et al. (2006) found no association between polymorphisms in the CST3 gene and AD.
A nonsynonymous 73G/A polymorphism in exon 1 of CST3 results in a penultimate A25T missense change (604312.0002) in the signal peptide (Radde et al., 2006). The CST3 thr25 allele has been associated with an increased risk of Alzheimer disease (Finckh et al., 2000; Cathcart et al., 2005; Bertram et al., 2007). It has been suggested that the thr25 variant impairs intracellular cystatin C processing, resulting in impaired secretion and reduced levels of extracellular cystatin C in the plasma of thr25 allele carriers. Kaeser et al. (2007) showed that overexpression of human cystatin C in brains of amyloid-beta precursor protein (APP; 104760) transgenic mice reduces cerebral amyloid-beta deposition and that cystatin C binds amyloid-beta and inhibits fibril formation. The results suggested that cystatin C concentrations modulate cerebral amyloidosis risk and provided an opportunity for genetic risk assessment and therapeutic interventions.
Mi et al. (2007) crossed transgenic mice overexpressing human CST3 with mice overexpressing human APP. They showed that cystatin C binds soluble amyloid-beta peptide and inhibits its cerebral amyloid deposition. Mi et al. (2007) hypothesized that endogenous cystatin C is a carrier of soluble amyloid-beta in cerebral spinal fluid, blood, and brain, where it inhibits amyloid-beta aggregation into insoluble plaques.
Age-Related Macular Degeneration 11
In a case-control study, Zurdel et al. (2002) investigated whether haplotypes A or B (A25T; 604312.0002) of CST3 were genetically associated with exudative age-related macular degeneration (611953) in a Caucasian population. They found that A25T (variant B) may be a recessive risk allele, significantly contributing to disease risk in up to 6.6% of German ARMD patients.
Butler et al. (2015) performed a case-control analysis of the CST3 A25T (c.73G-A) variant in 350 Caucasian British patients with ARMD, using 3,781 exomes from the Exome Sequencing Project as population controls. Although the result was not significant at an alpha level of 0.05, homozygotes were at greater risk of ARMD than heterozygotes. Combining their data with that of a previously reported association study (Zurdel et al., 2002), the evidence for a recessive effect on AMD risk was strengthened (odds ratio, 1.89; p = 0.005). Butler et al. (2015) suggested that common variants with a recessive effect account for some of the 'missing heritability' of multifactorial disease, which genomewide association studies may be underpowered to detect.
In patients with Icelandic-type cerebroarterial amyloidosis (105150), Abrahamson et al. (1987) identified a 358T-A transversion in the CST3 gene, resulting in a leu68-to-gln (L68Q) substitution. Palsdottir et al. (1988) used restriction site analysis to show that the heterozygous L68Q mutation segregated with the disorder in 8 families.
Abrahamson et al. (1992) described a rapid and simple method of diagnosis of Icelandic-type cerebroarterial amyloidosis based on oligonucleotide-directed enzymatic amplification of a 275-bp genomic DNA segment containing exon 2 of the cystatin C gene from a blood sample, followed by digestion of the amplification product with AluI. Loss of an AluI recognition site in the amplified DNA segment from patients resulted in a deviating band-pattern on agarose gel electrophoresis. Affected members of 4 different families all had the L68Q mutation.
Using in vitro functional analysis, Abrahamson and Grubb (1994) found that mutant L68Q cystatin C protein effectively inhibited the cysteine protease cathepsin B (116810), but started to dimerize and lose biologic activity immediately after it was transferred to a nondenaturing buffer. The dimerization was highly temperature-dependent, with a rise in incubation temperature from 37 to 40 degrees centigrade resulting in a 150% increase in dimerization rate. The aggregation at physiologic concentrations was increased at 40 degrees compared to 37 degrees C, by approximately 60%. Abrahamson and Grubb (1994) suggested that medical intervention to abort febrile periods in carriers of the disease trait might reduce the in vivo formation of L68Q cystatin C aggregates.
In a case-control study, Zurdel et al. (2002) investigated whether haplotypes A or B (A25T) of CST3 were genetically associated with exudative age-related macular degeneration (611953) in a Caucasian population. There was a significant difference in genotype counts between patients and controls, which could be explained completely by an excess of the homozygous CST3 genotype B/B in patients (6.6%) over controls (2.3%), suggesting an odds ratio for ARMD in association with CST3 B/B of 2.97 (95% CI, 1.28-6.86). Zurdel et al. (2002) concluded that A25T may be a recessive risk allele, significantly contributing to disease risk in up to 6.6% of German ARMD patients.
Butler et al. (2015) performed a case-control analysis of the CST3 A25T variant (rs1064039) in 350 Caucasian British patients with ARMD, using 3,781 exomes from the Exome Sequencing Project as population controls. Although the result was not significant at an alpha level of 0.05, homozygotes (AA) were at greater risk of ARMD than heterozygotes (GA). Combining their data with that of a previously reported association study (Zurdel et al., 2002), the evidence for a recessive effect on AMD risk was strengthened (odds ratio, 1.89; p = 0.005).
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