Mutation of human keratin 18 in association with cryptogenic cirrhosis.

Mutations in 11 of the more than 20 keratin intermediate filaments cause several epidermal and oral associated diseases. No disease-associated mutations have been described in keratin 8 or 18 (K8/18) which are the major keratin pair in simple-type epithelia, as found in the liver, pancreas, and intestine. However, transgenic mice that express mutant keratin 18 develop chronic hepatitis, and have an increased susceptibility to drug-induced hepatotoxicity. Also, ectopic expression of epidermal K14 in mouse liver results in chronic hepatitis, and disruption of mouse K8 leads to embryo lethality with extensive liver hemorrhage. We tested if patients with liver disease of unknown cause may harbor mutations in K18. We describe a his127-->leu (H127L) K18 mutation in a patient with cryptogenic cirrhosis that is germline transmitted. The K18 H127L isolated from the liver explant, or after expression in bacteria, showed an altered migration on two-dimensional gel analysis as compared with normal human liver or bacterially expressed K18. Electron microscopy of in vitro assembled K18 H127L and wild type K8 showed an assembly defect as compared with normal K8/18 assembly. Our results suggest that mutations in K18 may be predispose to, or result in cryptogenic cirrhosis in humans.

[1]  M. Omary,et al.  Susceptibility to hepatotoxicity in transgenic mice that express a dominant-negative human keratin 18 mutant. , 1996, The Journal of clinical investigation.

[2]  M. Omary,et al.  Chronic hepatitis, hepatocyte fragility, and increased soluble phosphoglycokeratins in transgenic mice expressing a keratin 18 conserved arginine mutant , 1995, The Journal of cell biology.

[3]  E. Lane,et al.  A mutation in the mucosal keratin K4 is associated with oral white sponge nevus , 1995, Nature Genetics.

[4]  S. Bale,et al.  Keratin 13 point mutation underlies the hereditary mucosal epithelia disorder white sponge nevus , 1995, Nature Genetics.

[5]  E. Lane,et al.  Temperature sensitivity of the keratin cytoskeleton and delayed spreading of keratinocyte lines derived from EBS patients. , 1995, Journal of cell science.

[6]  J. Rothnagel,et al.  Mutation of a type II keratin gene (K6a) in pachyonychia congenita , 1995, Nature Genetics.

[7]  E. Lane,et al.  Keratin 16 and keratin 17 mutations cause pachyonychia congenita , 1995, Nature Genetics.

[8]  M. Omary,et al.  The 70-kDa Heat Shock Proteins Associate with Glandular Intermediate Filaments in an ATP-dependent Manner (*) , 1995, The Journal of Biological Chemistry.

[9]  K. Albers,et al.  Expression of an epidermal keratin protein in liver of transgenic mice causes structural and functional abnormalities , 1995, The Journal of cell biology.

[10]  E. Lane,et al.  Intermediate filaments in disease. , 1995, Current opinion in cell biology.

[11]  M. Justice,et al.  Characterization and chromosomal localization of the cornea-specific murine keratin gene Krt1.12. , 1994, The Journal of biological chemistry.

[12]  M. Omary,et al.  Identification of the major physiologic phosphorylation site of human keratin 18: potential kinases and a role in filament reorganization , 1994, The Journal of cell biology.

[13]  V. Kodali,et al.  Cryptogenic liver disease in the United States: further evidence for non-A, non-B, and non-C hepatitis. , 1994, The American journal of gastroenterology.

[14]  V. Meininger,et al.  Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. , 1994, Human molecular genetics.

[15]  E. Fuchs,et al.  Cracks in the foundation: keratin filaments and genetic disease. , 1994, Trends in cell biology.

[16]  M. Nozaki,et al.  The complete sequence of the gene encoding mouse cytokeratin 15. , 1994, Gene.

[17]  K Weber,et al.  Intermediate filaments: structure, dynamics, function, and disease. , 1994, Annual review of biochemistry.

[18]  W. Franke,et al.  Molecular characterization of the body site-specific human epidermal cytokeratin 9: cDNA cloning, amino acid sequence, and tissue specificity of gene expression. , 1993, Differentiation; research in biological diversity.

[19]  S. Bale,et al.  Genetic skin diseases caused by mutations in keratin intermediate filaments. , 1993, Trends in genetics : TIG.

[20]  H. Baribault,et al.  Mid-gestational lethality in mice lacking keratin 8. , 1993, Genes & development.

[21]  R. Leube,et al.  Characterization of the human gene encoding cytokeratin 17 and its expression pattern. , 1992, European journal of cell biology.

[22]  E. Fuchs,et al.  Of mice and men: Genetic skin diseases of keratin , 1992, Cell.

[23]  Elaine Fuchs,et al.  Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: Genetic and functional analyses , 1991, Cell.

[24]  E. Fuchs,et al.  Mutant keratin expression in transgenic mice causes marked abnormalities resembling a human genetic skin disease , 1991, Cell.

[25]  R. Moll,et al.  Identification of protein IT of the intestinal cytoskeleton as a novel type I cytokeratin with unusual properties and expression patterns , 1990, The Journal of cell biology.

[26]  D. Mischke,et al.  The N-, but not the C-terminal domains of human keratins 13 and 15 are closely related. , 1989, Nucleic acids research.

[27]  D. Kulesh,et al.  Posttranslational regulation of keratins: degradation of mouse and human keratins 18 and 8 , 1989, Molecular and cellular biology.

[28]  W. Franke,et al.  Low level expression of cytokeratins 8, 18 and 19 in vascular smooth muscle cells of human umbilical cord and in cultured cells derived therefrom, with an analysis of the chromosomal locus containing the cytokeratin 19 gene. , 1988, European journal of cell biology.

[29]  J. Jorcano,et al.  Synthesis and fate of keratins 8 and 18 in nonepithelial cells transfected with cDNA. , 1988, Experimental cell research.

[30]  R. Leube,et al.  Molecular characterization and expression of the stratification-related cytokeratins 4 and 15 , 1988, The Journal of cell biology.

[31]  P M Steinert,et al.  Molecular and cellular biology of intermediate filaments. , 1988, Annual review of biochemistry.

[32]  J. Millán,et al.  Comparison of mouse and human keratin 18: a component of intermediate filaments expressed prior to implantation. , 1986, Differentiation; research in biological diversity.

[33]  E. Fuchs,et al.  Three tightly linked genes encoding human type I keratins: conservation of sequence in the 5'-untranslated leader and 5'-upstream regions of coexpressed keratin genes , 1986, Molecular and cellular biology.

[34]  E. Fuchs,et al.  Remarkable conservation of structure among intermediate filament genes , 1984, Cell.

[35]  Benjamin Geiger,et al.  The catalog of human cytokeratins: Patterns of expression in normal epithelia, tumors and cultured cells , 1982, Cell.