Keratin 8 mutations in patients with cryptogenic liver disease

Nam On Ku, Robert Gish, Teresa L. Wright, M. Bishr Omary

Research output: Contribution to journalArticle

128 Citations (Scopus)

Abstract

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. In transfected cells, the glycine-tocysteine 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.

Original languageEnglish
Pages (from-to)1580-1587
Number of pages8
JournalNew England Journal of Medicine
Volume344
Issue number21
DOIs
Publication statusPublished - 2001 May 24

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Keratin-8
Liver Diseases
Mutation
Keratin-18
Keratins
Glycine
Histidine
Genes
Keratin-2
Okadaic Acid
Hematology
Virus Diseases
Autoimmunity
Liver Transplantation
Cysteine
Tyrosine
Inpatients
Hepatocytes
Oxidative Stress
Outpatients

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Ku, Nam On ; Gish, Robert ; Wright, Teresa L. ; Omary, M. Bishr. / Keratin 8 mutations in patients with cryptogenic liver disease. In: New England Journal of Medicine. 2001 ; Vol. 344, No. 21. pp. 1580-1587.
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abstract = "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. In transfected cells, the glycine-tocysteine 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.",
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Keratin 8 mutations in patients with cryptogenic liver disease. / Ku, Nam On; Gish, Robert; Wright, Teresa L.; Omary, M. Bishr.

In: New England Journal of Medicine, Vol. 344, No. 21, 24.05.2001, p. 1580-1587.

Research output: Contribution to journalArticle

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T1 - Keratin 8 mutations in patients with cryptogenic liver disease

AU - Ku, Nam On

AU - Gish, Robert

AU - Wright, Teresa L.

AU - Omary, M. Bishr

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N2 - 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. In transfected cells, the glycine-tocysteine 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.

AB - 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. In transfected cells, the glycine-tocysteine 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.

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