Non-coding Keratin Variants Associate with Liver Fibrosis Progression in Patients with Hemochromatosis

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2012 Mar 14

PMID 22412904

Citations 5

Authors

Pavel Strnad

Ozlem Kucukoglu

Mariia Lunova

Nurdan Guldiken

Tim C Lienau

Felix Stickel

M Bishr Omary

Affiliations

Soon will be listed here.

Abstract

Background: Keratins 8 and 18 (K8/K18) are intermediate filament proteins that protect the liver from various forms of injury. Exonic K8/K18 variants associate with adverse outcome in acute liver failure and with liver fibrosis progression in patients with chronic hepatitis C infection or primary biliary cirrhosis. Given the association of K8/K18 variants with end-stage liver disease and progression in several chronic liver disorders, we studied the importance of keratin variants in patients with hemochromatosis.

Methods: The entire K8/K18 exonic regions were analyzed in 162 hemochromatosis patients carrying homozygous C282Y HFE (hemochromatosis gene) mutations. 234 liver-healthy subjects were used as controls. Exonic regions were PCR-amplified and analyzed using denaturing high-performance liquid chromatography and DNA sequencing. Previously-generated transgenic mice overexpressing K8 G62C were studied for their susceptibility to iron overload. Susceptibility to iron toxicity of primary hepatocytes that express K8 wild-type and G62C was also assessed.

Results: We identified amino-acid-altering keratin heterozygous variants in 10 of 162 hemochromatosis patients (6.2%) and non-coding heterozygous variants in 6 additional patients (3.7%). Two novel K8 variants (Q169E/R275W) were found. K8 R341H was the most common amino-acid altering variant (4 patients), and exclusively associated with an intronic KRT8 IVS7+10delC deletion. Intronic, but not amino-acid-altering variants associated with the development of liver fibrosis. In mice, or ex vivo, the K8 G62C variant did not affect iron-accumulation in response to iron-rich diet or the extent of iron-induced hepatocellular injury.

Conclusion: In patients with hemochromatosis, intronic but not exonic K8/K18 variants associate with liver fibrosis development.

Citing Articles

Molecular Modeling of Pathogenic Mutations in the Keratin 1B Domain.

Hinbest A, Eldirany S, Ho M, Bunick C Int J Mol Sci. 2020; 21(18).

PMID: 32927888 PMC: 7555247. DOI: 10.3390/ijms21186641.

Prevalence of genetic variants of keratins 8 and 18 in patients with drug-induced liver injury.

Usachov V, Urban T, Fontana R, Gross A, Iyer S, Omary M BMC Med. 2015; 13:196.

PMID: 26286715 PMC: 4545365. DOI: 10.1186/s12916-015-0418-0.

Emerging roles of sumoylation in the regulation of actin, microtubules, intermediate filaments, and septins.

Alonso A, Greenlee M, Matts J, Kline J, Davis K, Miller R Cytoskeleton (Hoboken). 2015; 72(7):305-39.

PMID: 26033929 PMC: 5049490. DOI: 10.1002/cm.21226.

Human keratin 8 variants promote mouse acetaminophen hepatotoxicity coupled with c-jun amino-terminal kinase activation and protein adduct formation.

Guldiken N, Zhou Q, Kucukoglu O, Rehm M, Levada K, Gross A Hepatology. 2015; 62(3):876-86.

PMID: 25963979 PMC: 4549164. DOI: 10.1002/hep.27891.

Keratin 8 variants are infrequent in patients with alcohol-related liver cirrhosis and do not associate with development of hepatocellular carcinoma.

Usachov V, Nahon P, Lunova M, Ziol M, Rufat P, Sutton A BMC Gastroenterol. 2012; 12:147.

PMID: 23078008 PMC: 3527286. DOI: 10.1186/1471-230X-12-147.

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