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At least 703 records · Page 39Linked to original sources
PubMed2006

Cleavage of cystatin C in the cerebrospinal fluid of patients with multiple sclerosis.

OBJECTIVE: The diagnosis of multiple sclerosis (MS) can be challenging because of the lack of a specific diagnostic test. Recent advances in proteomics, however, offer new opportunities for biomarker discovery and the study of disease pathogenesis. METHODS: We analyzed cerebrospinal fluid (CSF) samples from 29 patients with MS or clinically isolated syndromes (CIS), 27 patients with transverse myelitis (TM), 50 patients with human immunodeficiency virus (HIV) infection, and 27 patients with other neurological diseases (ONDs) by surface-enhanced laser desorption/ionization time-of-flight mass spectroscopy. RESULTS: We found a unique protein of 12.5 kDa that was 100% specific for MS/CIS compared with TM or OND. Low levels of this protein were found in some patients with HIV infection. Tandem mass spectroscopy of a tryptic digest of this 12.5 kDa protein identified it as a cleavage product of full-length cystatin C (13.4 kDa), an important inhibitor of cysteine proteases including the cathepsins. Although total cystatin C levels in the MS patients was not different compared with controls, the patients with the highest 12.5/13.4 peak ratios also had the greatest cathepsin B inhibitory activity. INTERPRETATION: This suggests that cleavage of cystatin C may be an adaptive host response and may identify a subgroup of patients with MS.

Adolescent↗
PubMed2007

Alteration of cystatin C in the cerebrospinal fluid of multiple sclerosis.

The protein profiles in the cerebrospinal fluid of 10 patients with multiple sclerosis (MS), 10 patients with neuromyelitis optica (NMO), 8 inflammatory disease control patients, and 4 noninflammatory disease control patients were screened by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Peaks of 12.5 kDa were significantly lower in multiple sclerosis, NMO, and inflammatory disease control patients than in noninflammatory disease control patients, and 13.4 kDa peaks were higher in NMO than in inflammatory disease control patients. Further analyses demonstrated that both peaks were cystatin C. Enzyme-linked immunosorbent assay showed that the cystatin C levels tended to be lower in multiple sclerosis and NMO. Alterations of cystatin C may relate to the pathogeneses of demyelinating diseases.

Cystatin C↗
PubMed2007

Cleavage of cystatin C is not associated with multiple sclerosis.

Recently, Irani and colleagues proposed a C-terminal cleaved isoform cystatin C (12.5 kDa) in cerebrospinal fluid as a marker of multiple sclerosis. In this study, we demonstrate that the 12.5 kDa product of cystatin C is formed by degradation of the first eight N-terminal residues. Moreover, such a degradation is not specific in the cerebrospinal fluid of multiple sclerosis, but rather is given by an inappropriate sample storage at -20 degrees C. We conclude that the use of the 12.5 kDa product of cystatin C in cerebrospinal fluid might lead to a fallacious diagnosis of multiple sclerosis. Preanalytical validation procedure is mandatory for proteomics investigations.

Artifacts↗
PubMed1997

Allelic heterogeneity of Mediterranean myoclonus and the cystatin B gene.

Mediterranean myoclonus is a progressive myoclonus epilepsy with autosomal recessive inheritance. Another form has been described in Finland, the so-called Baltic myoclonus. Mediterranean myoclonus and Baltic myoclonus are also known as Unverricht-Lundborg disease. Linkage analyses have shown that the genes for both these forms of myoclonus are closely linked to 21q22.3 DNA markers, suggesting that they are caused by mutations at the same locus (EPM1). Recently, two heterozygous mutations were found in the cystatin B gene in patients with Unverricht-Lundborg disease. We report recombinational and linkage disequilibrium mapping of EPM1, and cystatin B gene sequencing, in 14 consanguineous pedigrees with Mediterranean myoclonus. Linkage to 21q22.3 DNA markers was observed in all these families. Haplotype analysis suggests that a common mutation segregates within these pedigrees, and that this mutation is different from the common one responsible for the Finnish form of Unverricht-Lundborg disease. No mutation was found in the exons or splice junctions of the cystatin B gene in the 14 pedigrees.

Base Sequence↗
PubMed2005

The use of tryptic marker-peptides for the quantitative analysis of cystatin C.

The use of marker-peptides, measured by LC-MS/MS, is investigated for the quantitative analysis of proteins. To that end, cystatin C is chosen as a model protein. It not only functions as a proof of concept protein but the growing interest in cystatin C as a new marker of kidney failure provides a practical application at the same time. The use of trypsin-based proteolysis, to obtain so-called marker-peptides, simplifies the quantification of a protein to the quantification of a single or a number of peptides. Reproducibility of the trypsin proteolysis procedure is vital and has been optimised. A number of the marker-peptides obtained are selected for LC-MS(/MS) analysis. They are completely separated by high-pressure LC allowing maximum selectivity and mass spectrometric multiple reaction monitoring sensitivity. By doing so, linear calibration curves can be obtained for cystatin C over two orders of magnitude. Experiments have been performed on a triple quadrupole mass spectrometer by single ion monitoring (maximum sensitivity) as well as by multiple reaction monitoring (maximum specificity).

Amino Acid Sequence↗
PubMed2006

Cystatin C as a marker of renal function immediately after liver transplantation.

To verify whether cystatin C may be of some use as a renal function marker immediately after orthotopic liver transplantation (OLT), we compared serum cystatin C (S(Cyst)), serum creatinine (S(cr)), and creatinine clearance (C(cr)) levels with the glomerular filtration rate (GFR). On postoperative days 1, 3, 5, and 7, S(Cyst) and S(cr) was measured in simultaneously drawn blood samples, whereas C(cr) was calculated using a complete 24-hour urine collection. The GFR was determined on the same days by means of iohexol plasma clearance (I-GFR). The correlation between 1/S(Cyst) and I-GFR was stronger than that of 1/S(cr) or C(cr) (P< 0.01). In the case of moderate reductions in I-GFR (80-60 mL/minute/1.73 m), S(cr) remained within the normal range, whereas the increase in S(cyst) was beyond its upper limit; for I-GFR reductions to lower levels (59-40 mL/minute/1.73 m), S(cr) increased slightly, whereas S(cyst) was twice its upper normal limit. When we isolated all of the I-GFR values on days 3, 5, and 7 that were > or = 30% lower than that recorded on the first postoperative day, S(Cyst)(P< 0.0001) and S(cr) (P< 0.01) levels were increased, whereas C(cr) remained unchanged (P = 0.09). Receiver operating characteristic (ROC) area-under-the-curve analysis showed that the diagnostic accuracy of S(cyst) was better than that of S(cr) and C(cr). S(cyst) levels of 1.4, 1.7, and 2.2 mg/L respectively predicted I-GFR levels of 80, 60, and 40 mL/minute/1.73 m. In conclusion, cystatin C is a reliable marker of renal function during the immediate post-OLT period, especially when the goal is to identify moderate changes in GFR.

Adult↗
PubMed2004

Cystatin C as a potential cerebrospinal fluid marker for the diagnosis of Creutzfeldt-Jakob disease.

The definite diagnosis of Creutzfeldt-Jakob disease (CJD), the most common form of human prion diseases, relies upon neuropathological data usually obtained at autopsy. In living patients, the diagnosis, based on suggestive clinical features and EEG abnormalities, can be aided by the detection of altered levels of isoforms of the 14-3-3 protein in the cerebrospinal fluid (CSF). However, the validity of this test has been recently challenged and the search for other, more reliable biomarkers for CJD remains highly desirable. The present study describes the identification of a new potential surrogate marker in the CSF of CJD-affected patients. A preliminary study employing surface-enhanced laser desorption/ionization-time of flight (SELDI-TOF) technology highlighted a protein at 13.4 kDa in a small group (n = 8) of CJD-affected patients. Further analysis aimed at identifying this protein using cationic exchange chromatography, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed it to be cystatin C. Additional immunoblot assays confirmed that the level of cystatin C was significantly increased (p </= 0.05) in all tested samples (n = 8). We conclude that the analysis of cystatin C levels in CSF could be useful as a pre-mortem indicator of the disease.

Biomarkers↗
PubMed1992

Hereditary cystatin C amyloid angiopathy: identification of the disease-causing mutation and specific diagnosis by polymerase chain reaction based analysis.

Hereditary cystatin C amyloid angiopathy (HCCAA) is a dominantly inherited disease characterized by amyloidosis, dementia and fatal cerebral hemorrhage of young adults. A method for rapid and simple diagnosis of HCCAA is described. It is based upon 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 HCCAA patients results in a deviating band-pattern at agarose gel electrophoresis, compared with that obtained from normal subjects or unaffected HCCAA family members. In a population of 9 patients with manifest HCCAA, 14 patients with other causes of brain hemorrhage and 16 healthy individuals, the diagnostic procedure displayed a sensitivity and specificity for HCCAA of 100%. Amplified DNA segments from 4 HCCAA patients of four different families were analyzed by nucleotide sequencing; the HCCAA-causing mutation in all families was found to be a single T----A substitution in the codon for amino acid residue 68 of cystatin C.

Amino Acid Sequence↗
PubMed1990

Skin deposits in hereditary cystatin C amyloidosis.

Clinically normal skin from 47 individuals aged 9-70 years was investigated. Cystatin C amyloid deposits were found in various locations of the skin by light and/or electron microscopy, in all 12 patients with a clinical history of hereditary cystatin C amyloidosis (HCCA). Six asymptomatic individuals, who had the Alu 1 restriction fragment length polymorphism (RFLP) marker reported to cosegregate with the disease, also had cystatin C amyloid deposits in the skin. Three asymptomatic individuals (age 17-46) belonging to the HCCA families were without amyloid in the skin but had Alu 1 RFLP marker. Skin from 12 individuals who served as controls and skin from 14 close relatives of the patients was negative for amyloid. Punch biopsy of the skin is a simple procedure which is of value for the diagnosis of HCCA, even before the appearance of clinical symptoms. This method might also be of use in following progression of the disease.

Adolescent↗
PubMed2004

Cloning of a novel gene, Cymg1, related to family 2 cystatins and expressed at specific stages of mouse testis development.

We have cloned a novel gene, Cymg1 (GenBank accession number AY600990), from a mouse testis cDNA library. Cymg1 is located in 2G3 of mouse chromosome 2. The cDNA includes an open reading frame that encodes 141 amino acid residues. The encoded polypeptide has a cysteine protease inhibitor domain found in the family 2 cystatins but lacks critical consensus sites important for cysteine protease inhibition. These characteristics are seen in the proteins of the CRES subfamily of the family 2 cystatins which are expressed specifically in the reproductive tract. CYMG1 protein shows 44% identity with mouse CRES and 30% identity with mouse cystatin C. Northern blot analysis showed that the Cymg1 gene was specifically expressed in adult mouse testis. RT-PCR also showed that Cymg1 was expressed in testis and spermatogonial cells. Cymg1 expression level varied in the different developmental stages of mouse testis, and were coincidental with spermatogenesis and sex maturation. These results indicate that Cymg1 may play important roles in mouse spermatogenesis and sex maturation.

Amino Acid Sequence↗
PubMed2004

Increased cystatin C concentration in urine of nephrotic children.

The aim of this study was to evaluate changes in urine and plasma concentrations of cystatin C in children with a relapse of the idiopathic nephrotic syndrome(INS). The study group comprised 12 children with INS with proteinuria and 12 children in an 8-week remission,both treated with steroids. Twelve healthy children served as controls. Cystatin C was detectable in the urine of children with proteinuria. The study suggests that massive proteinuria may influence renal cystatin C handling.

Adolescent↗
PubMed2001

Expression of cathepsin B and cystatin C in human breast cancer.

Cathepsin B, which was originally found to be a lysosomal cysteine protease, is also an important matrix protease. In this study, we investigated the expression of cathepsin B and cystatin C, the strongest inhibitor of cathepsin B, and measured the relative amounts of each in human breast cancer tissues. Cystatin C expression relative to cathepsin B expression was found to be decreased. This finding could be associated with the looseness of cancerous interstitial tissue, which might play a role in cancer invasion and metastasis. This report documents the first simultaneous investigation of cathepsin B and cystatin C in breast cancer tissues.

Breast Neoplasms↗
PubMed1986

Hereditary cerebral amyloid angiopathy: the amyloid fibrils contain a protein which is a variant of cystatin C, an inhibitor of lysosomal cysteine proteases.

Hereditary Cerebral Hemorrhage With Amyloidosis is an autosomal dominant form of amyloidosis restricted to the cerebral vasculature. We have previously demonstrated that the amyloid protein subunit is similar to Cystatin C (or gamma-trace), an inhibitor of lysosomal cysteine proteinases, and homologous to kininogens. High pressure liquid chromatography tryptic fingerprint analysis was developed to distinguish Cystatin C from the amyloid protein. Moreover, we isolated and sequenced tryptic peptides in which the differences were detected. The data prove that the amyloid protein is 10 residues shorter than Cystatin C and has one amino acid substitution at residue 58.

Amino Acid Sequence↗
PubMed1988

Cathepsin D inactivates cysteine proteinase inhibitors, cystatins.

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. Inhibition must be the direct result of binding. On the contrary the interaction of cystatins with aspartic proteinase cathepsin D at pH 3.5 for 60 min followed by HPLC resulted in their inactivation accompanied by peptide bond cleavage at several sites, preferentially those involving hydrophobic amino acid residues. The released peptides do not inhibit papain and cathepsin L. These results explain reported elevated levels of cysteine proteinases and lead to the proposal that cathepsin D exerts an important function, through inactivation of cystatins, in the increased activities of cysteine proteinases in human diseases including muscular distrophy.

Amino Acid Sequence↗
PubMed1988

Human histidine-rich glycoprotein gene: evidence for evolutionary relatedness to cystatin supergene family.

The human chromosomal histidine-rich glycoprotein (HRG) gene has been isolated and its molecular structure was partially characterized. The gene is approximately 11 kb in length and contains nine exons and eight introns. Locations of the introns in HRG gene coding for cystatin domains are essentially identical with those of cystatin SN, SA and C, and kininogen genes. These results provide direct evidence that HRG belongs to a supergene family that includes cystatin SN, SA and C, and kininogen, and also demonstrate high conservation of the intron-exon organization among this supergene family.

Base Sequence↗
PubMed1990

Expression of the genes for transthyretin, cystatin C and beta A4 amyloid precursor protein in sheep choroid plexus during development.

The levels of mRNA for transthyretin, cystatin C, and beta A4 amyloid precursor protein were measured in the choroid plexus of sheep embryos during different stages of development, using specific cDNA probes and Northern blot analysis. The 3 different mRNAs were detectable in the brain of very young embryos with a crown-rump length of 1 cm, corresponding to only a few days of gestation. The choroid plexus increased in weight very rapidly in the first half of gestation and much more slowly in the second half. The level of transthyretin mRNA in choroid plexus increased during the first half of gestation and stayed constant thereafter until birth, at a level of about 70% of that in choroid plexus of adult sheep. The proportion of mRNA for the proteinase inhibitor cystatin C in total RNA from choroid plexus increased throughout gestation to adult levels at birth. The concentration of the mRNA for beta A4 amyloid precursor protein in choroid plexus early in development was already as high as in adults and remained at this level throughout gestation. Messenger RNA for cystatin C or mRNA for beta A4 amyloid precursor protein was not detected in adult sheep liver.

Amyloid beta-Peptides↗
PubMed1988

Cystatin C containing neurons in human postmortem hypothalamus.

The regional distribution and cellular localization of cystatin C in neurons of human postmortem hypothalamic was studied by use of peroxidase-anti-peroxidase technique. Cystatin C (earlier named gamma-trace) was found to be present in multiple nerve cells belonging to nuclei supraopticus, paraventricularis and arcuatus. We speculate that the occurrence of cystatin C in human cerebrospinal fluid is the result of a release of the protein from these neurons into the ventricular system.

Aged↗
PubMed1995

Bactericidal effect of rat cystatin S on an oral bacterium Porphyromonas gingivalis.

We tested antibacterial and antiviral activities of rat cystatin S, a cysteine proteinase inhibitor, belonging to the family 2 cystatins against 18 different bacterial species and poliovirus type 1 (Sabin). Rat cystatin S specifically inhibited the growth of a human oral anaerobic bacterium Porphyromonas gingivalis due to a bactericidal effect.

Amino Acid Sequence↗