Keratins as Susceptibility Genes for End-Stage Liver Disease.
In: Gastroenterology (00165085), Jg. 129 (2005-09-01), Heft 3, S. 885-893
Online
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Zugriff:
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. [Copyright &y& Elsevier]
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Keratins as Susceptibility Genes for End-Stage Liver Disease.
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Autor/in / Beteiligte Person: | 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 |
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Zeitschrift: | Gastroenterology (00165085), Jg. 129 (2005-09-01), Heft 3, S. 885-893 |
Veröffentlichung: | 2005 |
Medientyp: | academicJournal |
ISSN: | 0016-5085 (print) |
DOI: | 10.1053/j.gastro.2005.06.065 |
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