The molecular basis of hepcidin-resistant hereditary hemochromatosis.

摘要: The interaction between the hormone hepcidin and iron exporter ferroportin (Fpn) regulates plasma concentrations. Hepcidin binds to Fpn induces its internalization degradation, resulting in decreased efflux from cells into plasma. mutations N144, Y64N, C326 residue cause autosomal dominant disease with parenchymal overload, apparently due resistance of mutant hepcidin-mediated internalization. To define mechanism resistance, we generated human constructs bearing pathogenic mutations. mutants localized cell surface exported normally, but were partially or completely resistant continued export despite presence hepcidin. primary defect exofacial substitutions was loss binding, which resulted most severe phenotype. thiol form essential for hepcidin, suggesting that C326-SH homology is located near binding site In contrast, N144 Y64 residues not required their impaired subsequent ligand-receptor complex. Our observations explain why produce a hemochromatosis overload at an early age.