title: A novel missense mutation in SLC40A1 results in resistance to hepcidin and confirms the existence of two ferroportin-associated iron overload diseases.
abstract: Ferroportin-related iron overload disease differs from haemochromatosis in that it has a dominant mode of inheritance and is usually associated with macrophage iron sequestration. However, it is thought that mutations with opposite effects on protein functions, i.e. loss-of-function versus gain-of-function mutations, are responsible for variable phenotype presentations. The present study investigated the functional relevance of a novel ferroportin variant: the c.1502 A>G transition, which changes amino acid 501 from tyrosine to cysteine (p.Y501C). This novel variant was identified in a pedigree originating from Central Italy and, although an intra-familial phenotype heterogeneity was observed, it co-segregated with an iron overload picture similar to that of the HFE-related typical haemochromatosis. In cultured cells, the p.Y501C mutant protein reached the plasma membrane and retained a full iron export ability. By contrast, it was resistant to inhibition by hepcidin. These findings confirm that certain ferroportin mutations compromise the activity of hepcidin in iron homeostasis, mimicking hepcidin deficiency as described in all types of hemochromatosis.
authors.affiliation: Inserm U613, Etablissement Français du Sang - Bretagne, Université de Bretagne Occidentale, Brest, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Létocart
authors.forename: Gérald
authors.initials: G
authors.lastname: Le Gac
authors.forename: Silvia
authors.initials: S
authors.lastname: Majore
authors.forename: Chandran
authors.initials: C
authors.lastname: Ka
authors.forename: Francesca C
authors.initials: FC
authors.lastname: Radio
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gourlaouen
authors.forename: Carmelilia
authors.initials: C
authors.lastname: De Bernardo
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
authors.forename: Paola
authors.initials: P
authors.lastname: Grammatico
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D064451:Hepcidins; D006801:Humans; D019190:Iron Overload / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D013045:Species Specificity; D014162:Transfection; D000098742:Ferroportin
chemical_list: D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C578702:HAMP protein, human; D064451:Hepcidins; D000098742:Ferroportin