Mutation in Cystatin C Gene Causes Hereditary Brain Haemorrhage

Pálsdóttir, Ástrídur; Abrahamson, Magnus; Thorsteinsson, L.; Árnason, Arnar; Ólafsson, Ísleifur; Grubb, Anders; Jensson, O

doi:10.1016/s0140-6736(88)90641-1

Cited by 207 publications

(81 citation statements)

References 14 publications

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“…No reduction of the soluble wild-type cystatin C immunoreactivity could be demonstrated, not even after incubation for 1000 h at 40°C. DISCUSSION A mutation in the cystatin C gene produces the dominantly inherited disease HCCAA (8,11,12). However, the pathophysiological events relating this mutation to the salient features of the disease (systemic amyloid deposition of cystatin C and cerebral hemorrhage) are unknown.…”

Section: Resultsmentioning

confidence: 99%

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Increased body temperature accelerates aggregation ofthe Leu-68-->Gln mutant cystatin C, the amyloid-forming protein in hereditarycystatin C amyloid angiopathy.

Abrahamson

Grubb

1994

Proc. Natl. Acad. Sci. U.S.A.

127

110

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Hereditary cystatin C amyloid angiopathy is a dominantly inherited disorder, characterized by dementia, paralysis, and death from cerebral hemorrhage in early adult life. A variant of the cysteine proteinase inhibitor, cystatin C, is deposited as amyloid in the tissues of the patients and their spinal-fluid level of cystatin C is abnormally low. The diseaseassociated Leu-68 -* Gin mutant (L68Q) cystatin C has been produced in an Escherichia coi expression system and isolated by use of denaturing buffers, immunosorption, and gel fitration. Parallel physicochemical and functional investigations of L68Q-cystatin C and wild-type cystatin C revealed that both proteins effectively inhibit the cysteine proteinase cathepsin B (equilibrium constants for dissociation, 0.4 and 0.5 nM, respectively) but differ considerably in their tendency to dimerize and form aggregates. While wild-type cystatin C is monomeric and functionally active even after prolonged storage at elevated temperatures, L68Q-cystatin C starts to dimerize and lose biological activity immediately after it is transferred to a nondenaturing buffer. The dimerization of L68Q-cystatin C is highiy temperature-dependent, with a rise in incubation temperature from 37 to 40C resulting in a 150% increase in dimerization rate. The aggregation at physiological concentrations is likewise increased at 40 compared to 37C, by =60%. These properties of L68Q-cystatin C have bearing upon our understanding of the pathophysiological process of hereditary cystatin C amyloid angiopathy. They might also be of clinical relevance, since medical intervention to abort febrile periods of carriers of the disease trait may reduce the in vivo formation of L68Q-cystatin C aggregates.

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Section: Resultsmentioning

confidence: 99%

“…Furthermore, genetic studies have proven that the substitution demonstrated, Leu-68 --Gin (L68Q), corresponds to a mutation exclusively found in HCCAA patients' DNA (11,12). It is therefore likely that some intrinsic property of L68Q-cystatin C is directly responsible for the fatal consequences of the disease.…”

mentioning

confidence: 99%

Increased body temperature accelerates aggregation ofthe Leu-68-->Gln mutant cystatin C, the amyloid-forming protein in hereditarycystatin C amyloid angiopathy.

Abrahamson

Grubb

1994

Proc. Natl. Acad. Sci. U.S.A.

127

110

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“…Stroke susceptibility and resistance loci have been mapped in SHR. 64 Stroke susceptibility in humans also shows heritability ranging from Mendelian forms 65,66 to complex inheritance with familial aggregation. [67][68][69] Efforts to test functional candidate genes for stroke susceptibility in humans which is independent of blood pressure and hypertension status have begun with encouraging results.…”

Section: Independence Of Inheritance Of Hypertension Susceptibility Amentioning

confidence: 99%

Hypertension Genetics, Single Nucleotide Polymorphisms, and the Common Disease:Common Variant Hypothesis

Doris

2002

Hypertension

148

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Abstract-The investigation of heritable susceptibility to disease is an effort to associate disease phenotype with underlying genotype. Such genotype:phenotype associations have been demonstrated for a large number of monogenetic disorders. The usual strategy has been to use linkage mapping in affected families to identify chromosomal loci from which candidate genes and genotypes can be tested for association with disease. This strategy has not been similarly successful for common heritable disease susceptibilities including hypertension that involve multiple genes and gene-environment interactions. Development of extensive collections of single nucleotide polymorphisms (SNPs) raises the possibility that these SNPs can be used as markers in genome-wide association mapping studies to identify hypertension susceptibility loci. In this approach, large numbers of markers are typed in cases and controls with the expectation that markers interrogating SNPs that are involved in inheritance of disease susceptibility will emerge through their association with this trait in the affected population. Essential hypertension is a common disorder. The term "common" has 2 implications: first, that the disease is prevalent; and, second, that it is widespread. Such frequency and distribution characteristics could arise if the susceptibility alleles for hypertension were prevalent in the founding population of contemporary human beings and became distributed with human global dispersal. This common disease:common variant concept is attractive because it suggests that the genetic heterogeneity underlying hypertension susceptibility could be relatively small. It also allows the possibility that nonrandom association of alleles (linkage disequilibrium, LD) can be used to reduce the number of SNP markers required to identify disease susceptibility alleles because a single marker can act as a surrogate for variation flanking it. The influence of a number of important factors on the detectability of hypertension susceptibility alleles by SNP mapping approaches is not yet fully defined. These factors include the locus and allelic diversity of hypertension, the weaker relationship (compared with Mendelian traits) between genotype and phenotype, the accuracy of high throughput genotyping techniques, the extensive role of nongenetic factors, and the extent and heterogenous nature of LD across the genome.

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“…This small size inhibitor of cysteine proteinases is present in all human body fluids at physiologically relevant concentrations, being most abundant in the cerebrospinal fluid and in seminal plasma (Abrahamson et al, 1986). Although cystatin C in its wild-type form has not been reported to form amyloid in vivo, its Leu 68 3 Gln mutated variant (L68Q-cystatin C) is responsible for the dominantly inherited disorder called hereditary cystatin C amyloid angiopathy (Ghiso et al, 1986;Jensson et al, 1987;Palsdottir et al, 1988). Expression systems for both wild-type and L68Q-cystatin C have been developed (Dalbøge et al, 1989;Abrahamson and Grubb, 1994), and the three-dimensional structure of the human cystatin C-like type II cystatin, chicken cystatin, is well characterized by both x-ray crystallography and NMR spectroscopy (Bode et al, 1988;Engh et al, 1993).…”

mentioning

confidence: 99%

Folding-related Dimerization of Human Cystatin C

Ekiel

Abrahamson

1996

Journal of Biological Chemistry

122

101

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With the aim to improve our understanding of the structural basis for protein self-association and aggregation, in particular in relationship to protein refolding and amyloid formation, folding-related processes for human cystatin C have been studied. Using NMR spectroscopy together with chromatographic and electrophoretic methods, a self-association process resulting in dimer formation for protein samples treated with denaturing agents as well as for samples subjected to low pH or high temperature conditions could be studied with amino acid resolution. In all three cases, the dimerization involves properly folded molecules and proceeds via the reactive site of the inhibitor, which leads to complete loss of its biological activity. This dimerization process has potential relevance for amyloid formation by the brain hemorrhage-causing Leu 68 -Gln variant of cystatin C. The results also indicate that cystatin C dimerization and inactivation may occur in acidified compartments in vivo, which could be relevant for the physiological regulation of cysteine proteinase activity.The self-association and aggregation of proteins constitutes one of the least understood problems in protein chemistry.

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Mutation in Cystatin C Gene Causes Hereditary Brain Haemorrhage

Cited by 207 publications

References 14 publications

Increased body temperature accelerates aggregation ofthe Leu-68-->Gln mutant cystatin C, the amyloid-forming protein in hereditarycystatin C amyloid angiopathy.

Increased body temperature accelerates aggregation ofthe Leu-68-->Gln mutant cystatin C, the amyloid-forming protein in hereditarycystatin C amyloid angiopathy.

Hypertension Genetics, Single Nucleotide Polymorphisms, and the Common Disease:Common Variant Hypothesis

Folding-related Dimerization of Human Cystatin C

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