Afficher la couverture 'A new mutation in the hepcidin promoter impairs its BMP response and contributes to a severe phenotype in HFE related hemochromatosis. | Island, Marie-Laure' en grand format
/5

0 avis

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

Archive ouverte

Island, Marie-Laure | Jouanolle, Anne-Marie | Mosser, Annick | Deugnier, Yves | David, Véronique | Brissot, Pierre | Loréal, Olivier

Edité par CCSD ; Ferrata Storti Foundation -

International audience. 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.

Suggestions

Du même auteur

Ferroportin diseases: functional studies, a link between genetic and clinical phenotype.

Archive ouverte | Détivaud, Lénaïck | CCSD

International audience. Ferroportin (FPN) mediates iron export from cells and this function is modulated by serum hepcidin. Mutations in the FPN gene (SLC40A1) lead to autosomal dominant iron overload diseases relat...

Molecular diagnosis of genetic iron-overload disorders.

Archive ouverte | Brissot, Pierre | CCSD

International audience. Genetic iron overload has long been confined to the picture of classical hemochromatosis related to the HFE C282Y mutation (type 1 hemochromatosis). C282Y homozygosity affects approximately t...

GATA-4 transcription factor regulates hepatic hepcidin expression.

Archive ouverte | Island, Marie-Laure | CCSD

International audience. Hepcidin, an hormone mainly synthesized by hepatocytes and secreted in plasma, controls iron bioavailability. Thus, by inducing the internalization of the iron exporter ferroportin, it regula...

Chargement des enrichissements...