title: A new mutation in the hepcidin promoter impairs its BMP response and contributes to a severe phenotype in HFE related hemochromatosis.
abstract: Low levels of hepcidin are responsible for the development of iron overload in p.Cys282Tyr HFE related hemochromatosis. Every genetic factor lowering the hepcidin gene expression could contribute to a more severe phenotype in HFE hemochromatosis. Based on this hypothesis, we identified a heterozygous nc.-153 C>T mutation in the hepcidin gene promoter sequence in a patient homozygous for the p.Cys282Tyr HFE mutation who presented massive iron overload, resisting to well conducted iron depletive treatment. Our results demonstrate that the nc.-153 C>T mutation, located within a BMP-RE (Bone Morphogenetic Protein-Responsive Element): i) decreases the transcriptional activity of the hepcidin promoter, ii) alters its IL-6 (Interleukin-6) total responsiveness, and iii) prevents the binding of the SMAD protein complex (1/5/8 and 4) to the BPM-RE. In conclusion, our results suggest that a mutation in the BMP-RE of hepcidin promoter may impact on human iron metabolism.
authors.affiliation: INSERM U522, University of Rennes 1, Hôpital Pontchaillou, Rennes cedex, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Island
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Jouanolle
authors.forename: Annick
authors.initials: A
authors.lastname: Mosser
authors.forename: Yves
authors.initials: Y
authors.lastname: Deugnier
authors.forename: Véronique
authors.initials: V
authors.lastname: David
authors.forename: Pierre
authors.initials: P
authors.lastname: Brissot
authors.forename: Olivier
authors.initials: O
authors.lastname: Loréal
mesh_terms: D019943:Amino Acid Substitution; D023181:Antimicrobial Cationic Peptides / Q000235:genetics*; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D006432:Hemochromatosis / Q000175:diagnosis / Q000235:genetics*; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D014162:Transfection
chemical_list: D023181:Antimicrobial Cationic Peptides; D019485:Bone Morphogenetic Proteins; C578702:HAMP protein, human; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D008156:Luciferases