Keratins as susceptibility genes for end-stage liver disease

Nam On Ku, Joseph K. Lim, Sheri M. Krams, Carlos O. Esquivel, Emmet B. Keeffe, Teresa L. Wright, David A.D. Parry, M. Bishr Omary

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Abstract

Background & Aims: Keratins 8 and 18 protect the liver from stress. Keratin 8 and 18 variants in 17 of 467 liver disease explants and 2 of 349 blood bank controls were previously reported in 5 analyzed exonic regions. We asked whether mutations were present in the remaining 10 exons of keratins 8 and 18. Methods: Exonic regions were polymerase chain reaction-amplified from genomic DNA, isolated from the above-mentioned 2 cohorts, and analyzed for the presence of mutations. Mutant keratins were also studied biochemically. Results: We identified 10 novel keratin 8 and 18 heterozygous variants in 44 of 467 explants and 11 of 349 controls: keratin 18 deletion (Δ64-71), a keratin 8 frameshift that truncates the last 14 amino acids; 8 missense keratin 8 and 18 alterations; and several new polymorphisms. The most common variant, keratin 8 R340H, at the highly conserved R340 was found in 30 of 467 explants and 10 of 349 controls (P = .02) and was confirmed in the diseased livers by generation of an R340H-specific antibody. Germline transmission and variant protein expression were verified. The mutations involved a variety of liver diseases, and some variants had an ethnic background preponderance. Mutations that introduced disulfide bonds (keratin 8 G61C or R453C) decreased keratin solubility, particularly after oxidative stress, whereas others decreased keratin 8 phosphorylation (keratin 8 G433S). Conclusions: The overall frequency of keratin 8 and 18 variants was 12.4% in 467 liver disease explants and 3.7% in 349 blood bank controls (P < .0001). Variants can alter keratin solubility or phosphorylation and may render individuals susceptible to end-stage liver disease, depending on their genetic background and exposure to other insults, such as alcohol or viral infection.

Original languageEnglish
Pages (from-to)885-893
Number of pages9
JournalGastroenterology
Volume129
Issue number3
DOIs
Publication statusPublished - 2005 Sep

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

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    Ku, N. O., Lim, J. K., Krams, S. M., Esquivel, C. O., Keeffe, E. B., Wright, T. L., Parry, D. A. D., & Omary, M. B. (2005). Keratins as susceptibility genes for end-stage liver disease. Gastroenterology, 129(3), 885-893. https://doi.org/10.1053/j.gastro.2005.06.065