RESUMO
Hereditary cystatin C amyloid angiopathy is a dominantly inherited disease caused by a leucine to glutamine variant of human cystatin C (hCC). L68Q-hCC forms amyloid deposits in brain arteries associated with micro-infarcts, leading ultimately to paralysis, dementia and death in young adults. To evaluate the ability of molecules to interfere with aggregation of hCC while informing about cellular toxicity, we generated cells that produce and secrete WT and L68Q-hCC and have detected high-molecular weight complexes formed from the mutant protein. Incubations of either lysate or supernatant containing L68Q-hCC with reducing agents glutathione or N-acetyl-cysteine (NAC) breaks oligomers into monomers. Six L68Q-hCC carriers taking NAC had skin biopsies obtained to determine if hCC deposits were reduced following NAC treatment. Remarkably, ~50-90% reduction of L68Q-hCC staining was observed in five of the treated carriers suggesting that L68Q-hCC is a clinical target for reducing agents.
Assuntos
Acetilcisteína/farmacologia , Proteínas Amiloidogênicas/metabolismo , Angiopatia Amiloide Cerebral Familiar/dietoterapia , Cistatina C/metabolismo , Cistatinas/metabolismo , Acetilcisteína/administração & dosagem , Acetilcisteína/análogos & derivados , Acetilcisteína/química , Proteínas Amiloidogênicas/química , Proteínas Amiloidogênicas/genética , Biópsia , Angiopatia Amiloide Cerebral Familiar/tratamento farmacológico , Angiopatia Amiloide Cerebral Familiar/genética , Cistatina C/química , Cistatina C/genética , Cistatinas/química , Cistatinas/genética , Expressão Gênica , Glutationa/química , Glutationa/farmacologia , Células HEK293 , Humanos , Pele/efeitos dos fármacos , Pele/metabolismo , Adulto JovemRESUMO
A single founder mutation in each of the BRCA genes has been identified in Iceland. The frequency of the BRCA1 G5193A and BRCA2 999del5 mutations in all ovarian cancer patients diagnosed over the period 1991-2000 was determined. Mutation status was correlated with family history, tumour morphology and age at diagnosis. Samples from 86% of cases (179 carcinomas and 74 borderline tumours) were available. In the carcinomas, BRCA1 and BRCA2 mutations were present in 1.2% and 6% of cases, respectively. No BRCA mutations were found in the borderline tumours. Odds Ratio (OR) of developing ovarian cancer was 20.65 for BRCA2 carriers. Family history of breast/ovarian cancer was present for 70% of BRCA2 carriers and approximately 14% for non-carriers with carcinoma. In conclusion, BRCA2 999del5 is present in 6% of ovarian cancer cases in Iceland and is associated with a 20-fold increase in the risk of the disease. The BRCA1 G5193A mutation is too rare to contribute significantly to ovarian cancer in Iceland.