| 1. |
- Abrahamson, Magnus, et al.
(författare)
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Structure and expression of the human cystatin C gene
- 1990
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Ingår i: Biochemical Journal. - 1470-8728. ; 268:2, s. 287-294
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Tidskriftsartikel (refereegranskat)abstract
- The structural organization of the gene for the human cysteine-proteinase inhibitor cystatin C was studied. Restriction-endonuclease digests of human genomic DNA hybridized with human cystatin C cDNA and genomic probes produced patterns consistent with a single cystatin C gene and, also, the presence of six closely related sequences in the human genome. A 30 kb restriction map covering the genomic region of the cystatin C gene was constructed. The positions of three polymorphic restriction sites, found at examination of digests of genomic DNA from 79 subjects, were localized in the flanking regions of the gene. The gene was cloned and the nucleotide sequence of a 7.3 kb genomic segment was determined, containing the three exons of the cystatin C structural gene as well as 1.0 kb of 5'-flanking and 2.0 kb of 3'-flanking sequences. Northern-blot experiments revealed that the cystatin C gene is expressed in every human tissue examined, including kidney, liver, pancreas, intestine, stomach, antrum, lung and placenta. The highest cystatin C expression was seen in seminal vesicles. The apparently non-tissue-specific expression of this cysteine-proteinase inhibitor gene is discussed with respect to the structure of its 5'-flanking region, which shares several features with those of housekeeping genes.
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| 2. |
- Leion, Felicia, et al.
(författare)
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Estimating glomerular filtration rate (GFR) in children. The average between a cystatin C- and a creatinine-based equation improves estimation of GFR in both children and adults and enables diagnosing Shrunken Pore Syndrome.
- 2017
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Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 0036-5513 .- 1502-7686. ; 77:5, s. 338-344
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Tidskriftsartikel (refereegranskat)abstract
- Estimating glomerular filtration rate (GFR) in adults by using the average of values obtained by a cystatin C- (eGFRcystatin C) and a creatinine-based (eGFRcreatinine) equation shows at least the same diagnostic performance as GFR estimates obtained by equations using only one of these analytes or by complex equations using both analytes. Comparison of eGFRcystatin C and eGFRcreatinine plays a pivotal role in the diagnosis of Shrunken Pore Syndrome, where low eGFRcystatin C compared to eGFRcreatinine has been associated with higher mortality in adults. The present study was undertaken to elucidate if this concept can also be applied in children. Using iohexol and inulin clearance as gold standard in 702 children, we studied the diagnostic performance of 10 creatinine-based, 5 cystatin C-based and 3 combined cystatin C-creatinine eGFR equations and compared them to the result of the average of 9 pairs of a eGFRcystatin C and a eGFRcreatinine estimate. While creatinine-based GFR estimations are unsuitable in children unless calibrated in a pediatric or mixed pediatric-adult population, cystatin C-based estimations in general performed well in children. The average of a suitable creatinine-based and a cystatin C-based equation generally displayed a better diagnostic performance than estimates obtained by equations using only one of these analytes or by complex equations using both analytes. Comparing eGFRcystatin and eGFRcreatinine may help identify pediatric patients with Shrunken Pore Syndrome.
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| 3. |
- Malmgren, Linnea, et al.
(författare)
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The complexity of kidney disease and diagnosing it - Cystatin C, selective glomerular hypofiltration syndromes and proteome regulation.
- 2023
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Ingår i: Journal of Internal Medicine. - : John Wiley & Sons. - 0954-6820 .- 1365-2796. ; 293:3, s. 293-308
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Tidskriftsartikel (refereegranskat)abstract
- Estimation of kidney function is often part of daily clinical practice, mostly done by using the endogenous GFR-markers creatinine or cystatin C. A recommendation to use both markers in parallel in 2010 has resulted in new knowledge concerning the pathophysiology of kidney disorders by identification of a new set of kidney disorders, selective glomerular hypofiltration syndromes. These syndromes, connected to strong increases in mortality and morbidity, are characterised by a selective reduction in the glomerular filtration of 5-30 kDa molecules, such as cystatin C, compared to the filtration of small molecules < 1kDa dominating the glomerular filtrate e.g., water, urea, creatinine. At least two types of such disorders, shrunken or elongated pore syndrome, are possible according to the pore model for glomerular filtration. Selective glomerular hypofiltration syndromes are prevalent in investigated populations, and patients with these syndromes often display normal measured GFR or creatinine-based GFR-estimates. The syndromes are characterised by proteomic changes promoting the development of atherosclerosis, indicating antibodies and specific receptor-blocking substances as possible new treatment modalities. Presently, the KDIGO guidelines for diagnosing kidney disorders do not recommend cystatin C as a general marker of kidney function and will therefore not allow the identification of a considerable number of patients with selective glomerular hypofiltration syndromes. Furthermore, as cystatin C is uninfluenced by muscle mass, diet or variations in tubular secretion and cystatin C-based GFR-estimation equations do not require controversial race or sex terms, it is obvious that cystatin C should be a part of future KDIGO guidelines.
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| 4. |
- Sällman Almén, Markus, et al.
(författare)
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Shrunken Pore Syndrome Is Associated With Increased Levels of Atherosclerosis-Promoting Proteins
- 2019
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Ingår i: Kidney International Reports. - : Elsevier BV. - 2468-0249. ; 4:1, s. 67-79
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Shrunken pore syndrome (SPS), originally defined by cystatin C-based estimated glomerular filtration rate (eGFRcystatin C) being less than 60% of creatinine-based estimated glomerular filtration rate (eGFRcreatinine) in the absence of extrarenal influences on the plasma levels of cystatin C or creatinine, is associated with a high increase in mortality, even in the absence of reduced glomerular filtration rate (GFR). The objective of the present study was to determine whether the proteome of patients with SPS shows differences from that of patients with normal or reduced measured GFR (mGFR) without SPS.Methods: Four patient cohorts were included: 1 cohort with normal mGFR without SPS, 1 with normal mGFR with SPS, 1 with reduced mGFR without SPS, and 1 with reduced mGFR with SPS. The plasma levels of 177 selected proteins were analyzed.Results: Differences in the levels of 30 proteins were specific for SPS; 31 differences were specific for patients with both SPS and reduced mGFR; and 27 were specific for reduced mGFR. Eighteen of the differences specific for SPS concerned proteins described as promoting, or being associated with, atherosclerosis. Twelve of the differences specific for patients with both SPS and reduced mGFR and 10 of the differences specific for reduced mGFR also concerned proteins described as promoting, or being associated with, atherosclerosis. Almost all (82 of 88) of the concentration differences represented increased levels. For SPS, but not for reduced mGFR, a correlation between protein size and increase in level was observed, with smaller proteins being associated with higher levels.Conclusion: The high mortality in shrunken pore syndrome might be caused by the accumulation of atherosclerosis-promoting proteins in this condition.
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| 5. |
- Åkesson, Anna, et al.
(författare)
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Shrunken pore syndrome and mortality : a cohort study of patients with measured GFR and known comorbidities
- 2020
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Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 80:5, s. 412-422
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Tidskriftsartikel (refereegranskat)abstract
- Shrunken pore syndrome (SPS) is defined by a cystatin C-based estimation of glomerular filtration rate (eGFRCYS) being less than 60% or 70% of a creatinine-based GFR estimation (eGFRCR) in the absence of extrarenal influences on cystatin C or creatinine concentrations. SPS has been associated with a substantial increase in mortality or morbidity in all investigated populations. However, in these studies, neither the diagnoses, nor causes of death were described, and only estimated GFR was available. The present study concerns 2781 individuals with measured GFR (mGFR), known diagnoses, and known causes of death during 5.6 years in median. Cox multivariate proportional hazards regression model was used to estimate hazard ratios (HR) for all-cause and cancer, cardiovascular, diabetes or chronic kidney disease (CKD) as cause-specific mortality among patients with SPS. At an eGFRCYS/eGFRCR-ratio <0.70, the adjusted SPS death risk in the total cohort (HR 3.0, 95% CI 2.4-3.7) was clearly higher than that for the other diagnosis groups. In a sub-cohort of 1300 persons with or without diagnosis, but with normal mGFR, the all-cause mortality of SPS was markedly increased (HR 4.1, 95% CI 2.6-6.5). In a sub-cohort of 567 persons with normal mGFR and no diagnosis, the all-cause mortality of SPS was even more increased (HR 7.3, 95% CI 2.3-23). The prevalence of SPS in the total cohort was 23% and in the sub-cohorts 17 and 12%, respectively. As SPS is associated with a high mortality, occurs in the absence of reduced mGFR and albuminuria, it expands the spectrum of kidney disorders.
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| 6. |
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| 7. |
- Abrahamson, Magnus, et al.
(författare)
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Efficient production of native, biologically active human cystatin C by Escherichia coli
- 1988
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Ingår i: FEBS Letters. - 1873-3468. ; 236:1, s. 14-18
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Tidskriftsartikel (refereegranskat)abstract
- A cDNA encoding the mature human cysteine proteinase inhibitor cystatin C was fused to the coding sequence for the Escherichia coli outer membrane protein A signal peptide, and the recombinant gene was expressed in E. coli under the control of the λ PR promoter, an optimized Shine-Dalgarno sequence and the λ cI 857 repressor. When induced at 42°C, such cells expressed large amounts of recombinant cystatin C. The recombinant protein was isolated in high yield and characterized. All physicochemical properties investigated, including the positions of disulfide bonds, indicated that the E. coli derived cystatin C was identical to cystatin C isolated from human biological fluids, except that the proline residue in position three was not hydroxylated. The recombinant protein displayed full biological activity against papain, cathepsin B and dipeptidyl peptidase I.
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| 8. |
- Abrahamson, Magnus, et al.
(författare)
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Hereditary cystatin C amyloid angiopathy: Identification of the disease causing mutation and specific diagnosis by polymerase chain reaction based analysis
- 1992
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Ingår i: Human Genetics. - 1432-1203. ; 89:4, s. 377-380
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Tidskriftsartikel (refereegranskat)abstract
- 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 TrarrA substitution in the codon for amino acid residue 68 of cystatin C.
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| 9. |
- Abrahamson, Magnus, et al.
(författare)
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Human cystatin C: Role of the N-terminal segment in the inhibition of human cysteine proteinases and in its inactivation by leucocyte elastase
- 1991
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Ingår i: Biochemical Journal. - 0264-6021. ; 273:3, s. 621-626
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Tidskriftsartikel (refereegranskat)abstract
- Leucocyte elastase in catalytic amounts was observed to rapidly cleave the Val-10-Gly-11 bond of the human cysteine-proteinase inhibitor cystatin C at neutral pH. The resulting modified inhibitor had size and amino acid composition consistent with a cystatin C molecule devoid of the N-terminal Ser-1-Val-10 decapeptide. Leucocyte-elastase-modified cystatin C had more than 240-fold lower affinity than native cystatin C for papain. Removal of the N-terminal decapeptide of human cystatin C also decreased inhibition of human cathepsins B and L by three orders of magnitude, but decreased inhibition of cathepsin H by only 5-fold. A tripeptidyldiazomethane analogue of of the N-terminal portion of cystatin C was a good inhibitor of cathepsins B and L but a poor inhibitor of cathepsin H. It therefore appears that amino acid side chains of the N-terminal segment of cystatin C bind in the substrate-binding pockets of cathepsins B and L but not in those of cathepsin H. It is argued that the N-terminal cystatin C interaction with cathepsin B is physiologically important and hence that leucocyte elastase could have a function as a regulator of extracellular cysteine-proteinase inhibitory activity at sites of inflammation.
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| 10. |
- Abrahamson, Magnus, et al.
(författare)
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Identification of the probable inhibitory reactive sites of the cysteine proteinase inhibitors human cystatin C and chicken cystatin
- 1987
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 262:20, s. 9688-9694
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Tidskriftsartikel (refereegranskat)abstract
- When an excess of human cystatin C or chicken cystatin was mixed with papain, an enzyme-inhibitor complex was formed immediately. The residual free cystatin was then progressively converted to a form with different electrophoretic mobility and chromatographic properties. The modified cystatins were isolated and sequenced, showing that there had been cleavage of a single peptide bond in each molecule: Gly11-Gly12 in cystatin C, and Gly9-Ala10 in chicken cystatin. The residues Gly11 (cystatin C) and Gly9 (chicken cystatin) are among only three residues conserved in all known sequences of inhibitory cystatins. The modified cystatins were at least 1000-fold weaker inhibitors of papain than the native cystatins. An 18-residue synthetic peptide corresponding to residues 4-21 of cystatin C did not inhibit papain but was cleaved at the same Gly-Gly bond as cystatin C. When iodoacetate or L-3-carboxy- trans-2,3-epoxypropionyl-leucylamido-(4-guanidin o)butane was added to the mixtures of either cystatin with papain, modification of the excess cystatin was blocked. Papain-cystatin complexes were stable to prolonged incubation, even in the presence of excess papain. We conclude that the peptidyl bond of the conserved glycine residue in human cystatin C and chicken cystatin probably is part of a substrate- like inhibitory reactive site of these cysteine proteinase inhibitors of the cystatin superfamily and that this may be true also for other inhibitors of this superfamily. We also propose that human cystatin C and chicken cystatin, and probably other cystatins as well, inhibit cysteine proteinases by the simultaneous interactions with such proteinases of the inhibitory reactive sites and other, so far not identified, areas of the cystatins. The cleavage of the inhibitory reactive site glycyl bond in mixtures of papain with excess quantities of cystatins is apparently due to the activity of a small percentage of atypical cysteine proteinase molecules in the papain preparation that form only very loose complexes with cystatins under the conditions employed and degrade the free cystatin molecules.
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