Disease relevance of CST3

• AIMS: To determine whether allelic variants of the cystatin C gene CST3 are genetically associated with exudative age related macular degeneration (ARMD) [1].
• All the 3 cysteine proteinase inhibitors, ACPI, NCPI, and gamma-trace, were detected in pooled serum samples of patients with kidney failure. gamma-Trace seemed to be quantitatively the major and ACPI the minor inhibitor [2].
• The concentration of beta-2-microglobulin (beta 2-m) and of post gamma globulin (P gamma G) was examined in serum and cerebrospinal fluid from children with acute lymphatic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) [3].
• gamma-trace in human pituitary adenomas [4].
• FSH, TSH, and ACTH were each found in one gamma-trace-containing adenoma. gamma-Trace was also demonstrated in extracts of 1 pituitary adenoma and of 5 nontumorous adenohypophyses [4].

Psychiatry related information on CST3

• In the present study we attempted to determine the association between CST3 polymorphism and AD or vascular dementia (VD), and whether such effects are dependent of the APOE4 allele [5].
• A polymorphism in the cystatin C (CST3) gene was suggested to associate with Alzheimer's disease (AD) [5].

High impact information on CST3

• Gamma-trace immunoreactivity was noted in many A4-positive microvessel walls, but staining was always less intense than with the anti-A4 antibody [6].
• In the present multicentric electroencephalographic (EEG) study, we analyzed the effects of CST3 haplotypes on resting cortical rhythmicity in subjects with AD and mild cognitive impairment (MCI) with the hypothesis that sources of resting EEG rhythms are more impaired in carriers of the CST3 B haplotype than non-carriers [7].
• Results showed that the amplitude of alpha 1 (parietal, occipital, temporal areas) and alpha 2 (occipital area) was statistically lower in CST3 B carriers than non-carriers (P < 0.01) [7].
• The present findings represent the first demonstration of relationships between the AD genetic risk factor CST3 B and global neurophysiological phenotype (i.e., cortical delta and alpha rhythmicity) in MCI and AD subjects, prompting future genotype-EEG phenotype studies for the early prediction of AD conversion in individual MCI subjects [7].
• The authors could not confirm the previously reported association between CST3 polymorphisms and AD in Japan. Age had no effect on the CST3 genotype [8].

Biological context of CST3

• The human cystatin C gene (CST3) is a member of the cystatin gene family which is localized on chromosome 20 [9].
• RESULTS: The authors find a signficant interaction between the GG genotype of CST3 and age/age of onset on risk for AD, such that in the over-80 age group the GG genotype contributes two-fold increased risk for the disease [10].
• Associations between polymorphisms of the cystatin C gene (CST3) at 5' flanking region and exon 1 in Caucasian patients with late onset AD and exon 1 in a US study of late onset AD have been reported [8].
• CONCLUSION: Genotyping data, the absence of a significant difference in allele frequencies between patients and controls, and survival analyses suggest an increased susceptibility for ARMD in CST3 B/B homozygotes [1].
• No significant differences in CST3 genotype or allele frequencies between cases and controls was observed, while the risk of AD increased in subjects carrying the APOE epsilon4 allele (OR 3.5, 95% CI [2.1-5.9]) [11].

Anatomical context of CST3

• We performed CysC analysis on human primary skin fibroblasts obtained from donors carrying A/A, A/B, and B/B CST3 [12].
• BACKGROUND: Cystatin C (CST3), a strong inhibitor of cysteine proteinases, is freely filtered by the kidney glomerulus and is reabsorbed by the tubules, where it is almost totally catabolized, with the remainder then eliminated in urine [13].
• Post-gamma globulin previously isolated and partially sequenced in this laboratory was used for production of polyclonal and monoclonal (hybridoma) antibodies [14].
• Occurrence of beta2-microglobulin and post-gamma globulin in human semen [15].
• Gamma-trace immunostaining was more prominent on the adventitial component of arteriolar walls, whereas A4 staining was usually seen more diffusely throughout the blood vessel wall, especially in the media [16].

Associations of CST3 with chemical compounds

• The cystatin C gene (CST3) encodes a low-molecular-weight cysteine proteinase inhibitor belonging to family II of the cystatin superfamily and is mutated in cases of hereditary cystatin C amyloid angiopathy (HCCAA) [17].
• An Ala/Thr variation in the coding region of the human cystatin C gene (CST3) detected as a SstII polymorphism [18].
• gamma-Trace was demonstrated by the immunohistochemical peroxidase/anti-peroxidase technique to occur in normal chromaffin cells of the adrenal medulla from African green monkey, capuchin monkey and beagle dog and in the cells of a norepinephrine-producing human phaeochromocytoma [19].

Other interactions of CST3

• The association of CST3 B/B with AD was independent of APOE epsilon4; both genotypes independently reduced disease-free survival [20].
• OBJECTIVE: To determine whether the cystatin C gene (CST3) is genetically associated with late-onset Alzheimer disease (AD) [20].
• We screened the cystatin C gene (CST3) for mutations in 57 sporadic ALS patients and 12 familial ALS cases that did not possess a SOD1 mutation [21].
• The NR2 hybrid allowed us to exclude three candidate genes for AGS: hepatic nuclear factor 3 beta (HNF3 beta), paired box 1 (PAX1), and cystatin C (CST3) as shown by their localization outside of the deletion [22].
• To shed light on the catabolism of post-gamma globulin the levels of beta 2-microglobulin were also measured radiometrically [14].

Analytical, diagnostic and therapeutic context of CST3

• The region on chromosome 20 includes a strong candidate gene, cystatin C (CST3), which has previously been associated with AD in case-control studies [23].
• To investigate the genomic organization on chromosome 20, the CST3 gene and related sequences were regionally mapped by fluorescence in situ hybridization (FISH), Southern blot, and pulsed-field gel electrophoresis (PFGE) analysis using the cDNA cystatin C probe C6a and three genomic probes, C3E1, C3E2, and C3E2-2 [17].
• Method: The polymorphisms of the CST3 genotype were determined using PCR followed by restriction fragment length polymorphism analysis, and the plasma cystatin C concentrations were quantified by sandwich ELISA in 175 AD and 461 control subjects [24].
• The polymorphisms of CST3 genotype were determined using polymerase chain reactions (PCR) followed by gel electrophoresis in 124 AD, 70 VD, and 115 control individuals [5].
• A radioimmunoassay method was developed for quantitation of post-gamma globulin with either antibody [14].

References