CST3 – ACys Amyloidosis

Hereditary cystatin C amyloid angiopathy (HCCAA), also called ACys amyloidosis, is an autosomal dominant small-vessel amyloidosis characterized by progressive cerebral amyloid deposition, ischemic events, and fatal hemorrhagic strokes in young adults ([PMID:8737928]).

Genetic studies identified a single T→A substitution in codon 68 of CST3 (p.Leu68Gln), abolishing an AluI site and segregating with disease in multiple Icelandic families. In a cohort of nine manifest patients and in four unrelated families, the mutation was present in all affected individuals, with segregation in nine families and high penetrance ([PMID:1352269]; [PMID:8097919]). A founder effect is supported by a shared haplotype in 36 mutation carriers across nine pedigrees.

The variant spectrum is dominated by the recurrent p.Leu68Gln change; no other pathogenic CST3 alleles have been reported in ACys amyloidosis to date. Molecular diagnosis via RFLP or PCR-based assays allows rapid and specific detection of the founder mutation in presymptomatic and prenatal settings.

Functional analyses demonstrate that L68Q–cystatin C retains inhibitory activity against cathepsin B but exhibits markedly increased propensity for domain swapping, dimerization, and higher-order oligomerization at near-physiological temperatures ([PMID:8981667]). These oligomers serve as nucleation intermediates for amyloid fibril formation, recapitulating vascular deposition.

Cellular studies reveal that L68Q–cystatin C accumulates intracellularly in the endoplasmic reticulum of NIH/3T3 cells, impeding secretion and promoting local aggregation, which may contribute to vascular wall damage ([PMID:10193512]). In human cell models, secreted variant protein shows enhanced protease susceptibility and reduced cerebrospinal clearance, supporting in vivo depletion in patients ([PMID:9565605]).

Domain-swap stabilization via engineered disulfide bridges or antibody and papain-based inhibitors suppresses variant dimerization and amyloidogenesis in vitro, highlighting therapeutic targets to prevent pathogenic aggregate formation ([PMID:15028721]; [PMID:17470433]).

References

• Brain pathology (Zurich, Switzerland) • 1996 • The molecular pathology of hereditary cystatin C amyloid angiopathy causing brain hemorrhage. [PMID:8737928]
• Human genetics • 1992 • Hereditary cystatin C amyloid angiopathy: identification of the disease-causing mutation and specific diagnosis by polymerase chain reaction based analysis. [PMID:1352269]
• Biochemical medicine and metabolic biology • 1993 • Molecular diagnosis of hereditary cystatin C amyloid angiopathy. [PMID:8097919]
• Scandinavian journal of clinical and laboratory investigation. Supplementum • 1996 • Molecular basis for amyloidosis related to hereditary brain hemorrhage. [PMID:8981667]
• Molecular pathology : MP • 1998 • Intracellular accumulation of the amyloidogenic L68Q variant of human cystatin C in NIH/3T3 cells. [PMID:10193512]
• The Journal of biological chemistry • 1998 • Instability of the amyloidogenic cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type. [PMID:9565605]
• The Journal of biological chemistry • 2004 • Prevention of domain swapping inhibits dimerization and amyloid fibril formation of cystatin C: use of engineered disulfide bridges, antibodies, and carboxymethylpapain to stabilize the monomeric form of cystatin C. [PMID:15028721]
• The Journal of biological chemistry • 2007 • Fibrillogenic oligomers of human cystatin C are formed by propagated domain swapping. [PMID:17470433]

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