ArticlePloS one2012
Non-coding keratin variants associate with liver fibrosis progression in patients with hemochromatosis.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 13 citations in OpenAlex.
- Molecular Modeling of Pathogenic Mutations in the Keratin 1B Domain.International journal of molecular sciences · 2020Article
- Human keratin 8 variants promote mouse acetaminophen hepatotoxicity coupled with c-jun amino-terminal kinase activation and protein adduct formation.Hepatology (Baltimore, Md.) · 2015Article
- Prevalence of genetic variants of keratins 8 and 18 in patients with drug-induced liver injury.BMC medicine · 2015Article
- Emerging roles of sumoylation in the regulation of actin, microtubules, intermediate filaments, and septins.Cytoskeleton (Hoboken, N.J.) · 2015Review
- Keratin 8 variants are infrequent in patients with alcohol-related liver cirrhosis and do not associate with development of hepatocellular carcinoma.BMC gastroenterology · 2012Article
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundKeratins 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.
methodsThe 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.
resultsWe 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.
conclusionIn patients with hemochromatosis, intronic but not exonic K8/K18 variants associate with liver fibrosis development.
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