Submitted February 8, 2008
Accepted August 18, 2008
Down-regulation of hepcidin in porphyria cutanea tarda
Richard S. Ajioka*, John D Phillips, Robert B. Weiss, Diane M. Dunn, Maria W. Smit, Sean C. Proll, Michael G. Katze, and James P. Kushner
Division of Hematology, University of Utah School of Medicine, Salt Lake City, UT, United States
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, United States
Department of Microbiology, University of Washington School of Medicine, Seattle, WA, United States
* Corresponding author; email: richard.ajioka{at}hsc.utah.edu.
Hepatic siderosis is common in patients with porphyria cutanea tarda (PCT). Mutations in the hereditary hemochromatosis (hh) gene (HFE) explain the siderosis in approximately 20 percent of cases suggesting that the remaining cases result from additional genetic and environmental factors. Two genes known to modify iron loading in hh are hepcidin (HAMP) and hemojuvelin (HJV). To determine if mutations in or expression of these genes influenced iron overload in PCT, we compared sequences of HAMP and HJV in 96 patients with PCT and 88 HFE C282Y homozygotes with marked hepatic iron overload. We also compared hepatic expression of these and other iron-related genes in a group of PCT and hh patients. Two intronic polymorphisms in HJV were associated with elevated serum ferritin in HFE C282Y homozygotes. No exonic polymorphisms were identified. Sequencing of HAMP revealed exonic polymorphisms in two patients with PCT: heterozygosity for a G
A transition (G71D substitution) in one and heterozygosity for an AG transition (K83R substitution) in the other. Hepatic HAMP expression in PCT patients was significantly reduced, regardless of HFE genotype, when compared to hh patients with comparable iron overload. These data indicate that the hepatic siderosis associated with PCT likely results from dysregulated HAMP.
