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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.
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https://www.hal.inserm.fr/inserm-00372237
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Submitted on : Monday, April 6, 2009 - 2:04:54 PM
Last modification on : Wednesday, May 16, 2018 - 11:23:16 AM
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Marie-Laure Island, Anne-Marie Jouanolle, Annick Mosser, Yves Deugnier, Véronique David, et al.. A new mutation in the hepcidin promoter impairs its BMP response and contributes to a severe phenotype in HFE related hemochromatosis.. Haematologica, Ferrata Storti Foundation, 2009, 94 (5), pp.720-4. ⟨10.3324/haematol.2008.001784⟩. ⟨inserm-00372237⟩

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