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.
Highlights
Intermediate filaments (IFs), together with microtubules and the actin-containing microfilaments constitute the three major components of eukaryotic cytoskeleton [1]
We studied the role of keratin variants in patients with hereditary hemochromatosis (HHC)
All assessed parameters of iron metabolism were markedly higher in males compared to females (Table 1)
Summary
Intermediate filaments (IFs), together with microtubules and the actin-containing microfilaments constitute the three major components of eukaryotic cytoskeleton [1]. The simple hepatocellular keratin expression pattern accounts for the observation that animals either lacking K8/K18 or expressing mutant K8/K18 display a predominant hepatic phenotype [4]. These animal findings spurred human association studies, which identified K8/K18 variants to be overrepresented in patients with cryptogenic and non-cryptogenic liver cirrhosis [4]. Subsequent reports showed that the presence of K8/K18 variants predisposes to liver fibrosis development in patients with chronic hepatitis C and primary biliary fibrosis as well as to adverse outcome of acute liver failure [5,6,7]. 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 endstage liver disease and progression in several chronic liver disorders, we studied the importance of keratin variants in patients with hemochromatosis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
