Keratin 8 mutations in patients with cryptogenic liver disease

N Engl J Med. 2001 May 24;344(21):1580-7. doi: 10.1056/NEJM200105243442103.


Background: About 10 percent of patients who undergo liver transplantation have cryptogenic liver disease. In animal models, the absence of heteropolymeric keratins 8 and 18 or the presence of mutant keratins in hepatocytes causes or promotes liver disease. We have previously described a mutation in the keratin 18 gene in a patient with cryptogenic cirrhosis, but the importance of mutations in the keratin 8 and keratin 18 genes in such patients is unclear.

Methods: We tested for mutations in the keratin 8 and keratin 18 genes in purified genomic DNA isolated from 150 explanted livers and 89 peripheral-blood specimens from three groups of patients: 55 patients with cryptogenic liver disease; 98 patients with noncryptogenic liver disease, with causes that included alcohol use, autoimmunity, drug use, and viral infections; and 86 randomly selected inpatients and outpatients who provided blood to the hematology laboratory.

Results: Of the 55 patients with cryptogenic liver disease, 3 had glycine-to-cysteine mutations at position 61 (a highly conserved glycine) of keratin 8, and 2 had tyrosine-to-histidine mutations at position 53 of keratin 8. These mutations were not detected in the patients with other liver diseases or in the randomly selected patients. We verified the presence of the mutations in specimens of explanted livers by protein analysis and by the detection of unique restriction-enzyme cleavage sites. In transfected cells, the glycine-to-cysteine mutation limited keratin-filament reorganization when the cells were exposed to oxidative stress. In contrast, the tyrosine-to-histidine mutation destabilized keratin filaments when transfected cells were exposed to heat or okadaic acid stress.

Conclusions: Mutations in the keratin 8 gene may predispose people to liver disease and may account for cryptogenic liver disease in some patients.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Cell Line / chemistry
  • Cell Line / cytology
  • Cytoskeleton / pathology
  • DNA Mutational Analysis
  • Female
  • Fluorescent Antibody Technique
  • Hepatitis / genetics
  • Humans
  • Immunoblotting
  • Keratin-8
  • Keratins / analysis
  • Keratins / chemistry
  • Keratins / genetics*
  • Liver / chemistry
  • Liver Cirrhosis / ethnology
  • Liver Cirrhosis / genetics*
  • Liver Cirrhosis / surgery
  • Liver Transplantation
  • Male
  • Point Mutation*
  • Random Allocation
  • Transfection


  • KRT8 protein, human
  • Keratin-8
  • Keratins