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 Jan 1

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Keratin-8
End Stage Liver Disease
Keratins
Keratin-18
Genes
Liver Diseases
Blood Banks
Mutation
Solubility
Phosphorylation
Virus Diseases
Disulfides
Exons
Oxidative Stress

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Ku, N., Lim, J. K., Krams, S. M., Esquivel, C. O., Keeffe, E. B., Wright, T. L., ... 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
Ku, Nam-on ; Lim, Joseph K. ; Krams, Sheri M. ; Esquivel, Carlos O. ; Keeffe, Emmet B. ; Wright, Teresa L. ; Parry, David A.D. ; Omary, M. Bishr. / Keratins as susceptibility genes for end-stage liver disease. In: Gastroenterology. 2005 ; Vol. 129, No. 3. pp. 885-893.
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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.",
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Ku, N, Lim, JK, Krams, SM, Esquivel, CO, Keeffe, EB, Wright, TL, Parry, DAD & Omary, MB 2005, 'Keratins as susceptibility genes for end-stage liver disease', Gastroenterology, vol. 129, no. 3, pp. 885-893. https://doi.org/10.1053/j.gastro.2005.06.065

Keratins as susceptibility genes for end-stage liver disease. / Ku, Nam-on; Lim, Joseph K.; Krams, Sheri M.; Esquivel, Carlos O.; Keeffe, Emmet B.; Wright, Teresa L.; Parry, David A.D.; Omary, M. Bishr.

In: Gastroenterology, Vol. 129, No. 3, 01.01.2005, p. 885-893.

Research output: Contribution to journalArticle

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T1 - Keratins as susceptibility genes for end-stage liver disease

AU - Ku, Nam-on

AU - Lim, Joseph K.

AU - Krams, Sheri M.

AU - Esquivel, Carlos O.

AU - Keeffe, Emmet B.

AU - Wright, Teresa L.

AU - Parry, David A.D.

AU - Omary, M. Bishr

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N2 - 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.

AB - 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.

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Ku N, Lim JK, Krams SM, Esquivel CO, Keeffe EB, Wright TL et al. Keratins as susceptibility genes for end-stage liver disease. Gastroenterology. 2005 Jan 1;129(3):885-893. https://doi.org/10.1053/j.gastro.2005.06.065