title: Down-regulation of hepcidin in porphyria cutanea tarda.
abstract: 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% patients, suggesting that the remaining occurrences 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 patients with PCT and hh. 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 2 patients with PCT: heterozygosity for a G-->A transition (G71D substitution) in one and heterozygosity for an A-->G transition (K83R substitution) in the other. Hepatic HAMP expression in patients with PCT was significantly reduced, regardless of HFE genotype, when compared with patients with hh but without PCT with comparable iron overload. These data indicate that the hepatic siderosis associated with PCT likely results from dysregulated HAMP.
authors.affiliation: Division of Hematology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. richard.ajioka@hsc.utah.edu
authors.forename: Richard S
authors.initials: RS
authors.lastname: Ajioka
authors.forename: John D
authors.initials: JD
authors.lastname: Phillips
authors.forename: Robert B
authors.initials: RB
authors.lastname: Weiss
authors.forename: Diane M
authors.initials: DM
authors.lastname: Dunn
authors.forename: Maria W
authors.initials: MW
authors.lastname: Smit
authors.forename: Sean C
authors.initials: SC
authors.lastname: Proll
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
authors.forename: James P
authors.initials: JP
authors.lastname: Kushner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D023181:Antimicrobial Cationic Peptides / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D007223:Infant; D008107:Liver Diseases / Q000209:etiology / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D017119:Porphyria Cutanea Tarda / Q000150:complications / Q000235:genetics*; D012806:Siderosis / Q000209:etiology / Q000235:genetics; D055815:Young Adult
chemical_list: D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins