Journal
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
Volume 94, Issue 5, Pages 720-724Publisher
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2008.001784
Keywords
hepcidin bone morphogenetic protein; hemochromatosis; iron; gene expression
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Funding
- European Community Grant (Euroiron1) [LSHM-CT-2006-037296]
- Association Fer et Foie, the French National Centre for Rare Genetic Iron Overload Disorders
- Biological Ressources Centre of Rennes
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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.
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