Published online 13 March 2009
Haematologica, Vol 94, Issue 5, 720-724 doi:10.3324/haematol.2008.001784
Copyright © 2009 by Ferrata Storti Foundation
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Disorders of Iron Metabolism

A new mutation in the hepcidin promoter impairs its BMP response and contributes to a severe phenotype in HFE related hemochromatosis

Marie-Laure Island1, Anne-Marie Jouanolle2,3, Annick Mosser2,3, Yves Deugnier1,3,4, Véronique David2,3, Pierre Brissot1,3,4, Olivier Loréal1,3

1 Inserm U522, IFR140; University of Rennes 1
2 Molecular Genetic Department
3 French National Centre for Rare Genetic Iron Overload Diseases
4 Liver Disease Department, University Hospital Pontchaillou, Rennes, France

Correspondence: Olivier Loréal, INSERM U522, Hôpital Pontchaillou 35033 Rennes cedex, France. E-mail:olivier.loreal{at}univ-rennes1.fr

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.

Key words: hepcidin, BMP, hemochromatosis, iron, gene expression.




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