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Keratin 8 mutations in patients with cryptogenic liver disease
1Gastroenterology Section, Palo Alto Veterans Affairs Medical Center and Stanford University School of Medicine, Calif 94304, USA.
The New England Journal of Medicine
|May 24, 2001
Summary
Mutations in keratin 8 (KRT8) and keratin 18 (KRT18) genes are linked to cryptogenic liver disease. Specific KRT8 mutations were identified in patients, suggesting a predisposition to liver disease.
Area of Science:
- Hepatology
- Molecular Biology
- Genetics
Background:
- Cryptogenic liver disease affects approximately 10% of liver transplant recipients.
- Keratin 8 (KRT8) and keratin 18 (KRT18) mutations in hepatocytes can cause or exacerbate liver disease, as shown in animal models.
- Previous research identified a KRT18 mutation in a patient with cryptogenic cirrhosis, but the role of KRT8 and KRT18 mutations in these patients remained unclear.
Purpose of the Study:
- To investigate the prevalence and significance of mutations in the keratin 8 (KRT8) and keratin 18 (KRT18) genes in patients with cryptogenic liver disease.
- To determine if these mutations are specific to cryptogenic liver disease compared to other liver conditions.
Main Methods:
- Genomic DNA was extracted from 150 explanted livers and 89 peripheral-blood specimens.
- Patients were categorized into three groups: cryptogenic liver disease (n=55), noncryptogenic liver disease (n=98), and healthy controls (n=86).
- Keratin 8 (KRT8) and keratin 18 (KRT18) genes were analyzed for mutations using DNA sequencing and confirmed with protein analysis and restriction enzyme digestion.
Main Results:
- Five patients with cryptogenic liver disease exhibited mutations in the keratin 8 (KRT8) gene: three with glycine-to-cysteine at position 61 and two with tyrosine-to-histidine at position 53.
- These specific KRT8 mutations were absent in patients with noncryptogenic liver diseases and in the control group.
- Functional studies in transfected cells demonstrated that the glycine-to-cysteine mutation impaired keratin filament reorganization under oxidative stress, while the tyrosine-to-histidine mutation destabilized keratin filaments under heat or okadaic acid stress.
Conclusions:
- Mutations in the keratin 8 (KRT8) gene are associated with an increased susceptibility to liver disease.
- These KRT8 gene mutations may be a contributing factor to cryptogenic liver disease in a subset of patients.
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