A new mutation in the hepcidin promoter impairs its BMP response and contributes to a severe phenotype in HFE related hemochromatosis.
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.
Island
Marie-Laure
ML
INSERM U522, University of Rennes 1, Hôpital Pontchaillou, Rennes cedex, France.
Jouanolle
Anne-Marie
AM
Mosser
Annick
A
Deugnier
Yves
Y
David
Véronique
V
Brissot
Pierre
P
Loréal
Olivier
O
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
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