Genetics and Neuropathology of Hereditary Cystatin C Amyloid Angiopathy (HCCAA)

2000 ◽  
pp. 121-134
Author(s):  
Ísleifur Ólafsson ◽  
Leifur Thorsteinsson
Keyword(s):  
Cystatin C ◽  
Amyloid Angiopathy

scholarly journals Stabilization, Characterization, and Selective Removal of Cystatin C Amyloid Oligomers

2013 ◽  
Vol 288 (23) ◽  
pp. 16438-16450 ◽  
Author(s):  
Gustav Östner ◽  
Veronica Lindström ◽  
Per Hjort Christensen ◽  
Maciej Kozak ◽  
Magnus Abrahamson ◽  
...  
Keyword(s):  
Cystatin C ◽  
Amyloid Fibrils ◽  
Dynamic Equilibrium ◽  
Biological Fluids ◽  
Polyacrylamide Gel Electrophoresis ◽  
Gel Filtration ◽  
Domain Swapping ◽  
Amyloid Angiopathy ◽  
Force Microscopy ◽  
And Function

The pathophysiological process in amyloid disorders usually involves the transformation of a functional monomeric protein via potentially toxic oligomers into amyloid fibrils. The structure and properties of the intermediary oligomers have been difficult to study due to their instability and dynamic equilibrium with smaller and larger species. In hereditary cystatin C amyloid angiopathy, a cystatin C variant is deposited in arterial walls and cause brain hemorrhage in young adults. In the present investigation, we use redox experiments of monomeric cystatin C, stabilized against domain swapping by an intramolecular disulfide bond, to generate stable oligomers (dimers, trimers, tetramers, decamers, and high molecular weight oligomers). These oligomers were characterized concerning size by gel filtration, polyacrylamide gel electrophoresis, and mass spectrometry, shape by electron and atomic force microscopy, and, function by assays of their capacity to inhibit proteases. The results showed the oligomers to be highly ordered, domain-swapped assemblies of cystatin C and that the oligomers could not build larger oligomers, or fibrils, without domain swapping. The stabilized oligomers were used to induce antibody formation in rabbits. After immunosorption, using immobilized monomeric cystatin C, and elution from columns with immobilized cystatin C oligomers, oligomer-specific antibodies were obtained. These could be used to selectively remove cystatin C dimers from biological fluids containing both dimers and monomers.

No mutations in cystatin C gene in cerebral amyloid angiopathy with cystatin C deposition

1998 ◽  
Vol 33 (1) ◽  
pp. 63-78 ◽  
Author(s):  
Atsushi Nagai ◽  
Shotai Kobayashi ◽  
Koichi Shimode ◽  
Kaoru Imaoka ◽  
Nobuyuki Umegae ◽  
...  
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Cystatin C ◽  
Amyloid Angiopathy ◽  
Cerebral Amyloid

Cerebral Amyloid Angiopathy Associated with Cerebral Hemorrhage with the Deposition of Cystatin C: Study on Japanese Cases

1991 ◽  
pp. 365-368 ◽  
Author(s):  
S. Fujihara ◽  
K. Shimode ◽  
M. Nakamura ◽  
S. Kobayashi ◽  
T. Tsunematsu ◽  
...  
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Cystatin C ◽  
Cerebral Hemorrhage ◽  
Amyloid Angiopathy ◽  
Cerebral Amyloid

Molecular Diagnosis of Hereditary Cystatin C Amyloid Angiopathy

1993 ◽  
Vol 49 (2) ◽  
pp. 117-123 ◽  
Author(s):  
S. Jonsdottir ◽  
A. Palsdottir
Keyword(s):  
Molecular Diagnosis ◽  
Cystatin C ◽  
Amyloid Angiopathy

scholarly journals Stroke in Icelandic patients with hereditary amyloid angiopathy is related to a mutation in the cystatin C gene, an inhibitor of cysteine proteases.

1989 ◽  
Vol 169 (5) ◽  
pp. 1771-1778 ◽  
Author(s):  
E Levy ◽  
C Lopez-Otin ◽  
J Ghiso ◽  
D Geltner ◽  
B Frangione
Keyword(s):  
Amino Acids ◽  
Cystatin C ◽  
Cerebral Hemorrhage ◽  
Signal Sequence ◽  
Genetic Defect ◽  
Cysteine Proteases ◽  
Amyloid Angiopathy ◽  
Primary Defect ◽  
Gene Encoding ◽  
The Brain

Cystatin C is an inhibitor of lysosomal cysteine proteases and consists of 120 amino acids. A variant of cystatin C lacking the first NH2-terminal residues and having one amino acid substitution at position 68 forms amyloid deposits mainly in the walls of brain arteries, causing fatal strokes in Icelandic patients with familial cerebral hemorrhage secondary to a form of an autosomal dominant amyloidosis. To understand the molecular basis of the genetic defect, the gene encoding cystatin C was isolated from genomic DNA libraries made from normal tissue and the brain of an Icelandic patient with hereditary cerebral hemorrhage with amyloidosis (HCHWA-I). The data indicate that the cystatin C gene encodes a polypeptide of 146 amino acids, of which the first 26 correspond to a secretory peptide signal sequence. The gene contains two intervening sequences that interrupt the coding region at amino acids 55 and 93. Comparison with genes encoding salivary cystatins and kininogen proteins show sequence homology and conservation of exon-intron structure. Except for a mutation in the second exon (CAG instead of CTG in the normal gene, resulting in the substitution of glutamine for a leucine residue), the gene cloned from the brain of the Icelandic patient is identical to the normal cystatin C gene. Thus, HCHWA-I is the first familial type of amyloidosis related to a point mutation in a gene encoding for an inhibitor. The mutation in the structural gene encoding cystatin C appears to be the primary defect in this inherited disorder causing amyloid fibril formation and accumulation followed by cerebral hemorrhage.

Parenchymal cystatin C focal deposits and glial scar formation around brain arteries in Hereditary Cystatin C Amyloid Angiopathy

2015 ◽  
Vol 1622 ◽  
pp. 149-162 ◽  
Author(s):  
Asbjorg Osk Snorradottir ◽  
Helgi J. Isaksson ◽  
Stephan A. Kaeser ◽  
Angelos A. Skodras ◽  
Elias Olafsson ◽  
...  
Keyword(s):  
Cystatin C ◽  
Glial Scar ◽  
Scar Formation ◽  
Amyloid Angiopathy ◽  
Brain Arteries

scholarly journals Pathological changes in basement membranes and dermal connective tissue of skin from patients with hereditary cystatin C amyloid angiopathy

2017 ◽  
Vol 97 (4) ◽  
pp. 383-394 ◽  
Author(s):  
Asbjorg Osk Snorradottir ◽  
Helgi J Isaksson ◽  
Saevar Ingthorsson ◽  
Elias Olafsson ◽  
Astridur Palsdottir ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Cystatin C ◽  
Basement Membranes ◽  
Amyloid Angiopathy ◽  
Pathological Changes ◽  
Dermal Connective Tissue
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