Hereditary hemochromatosis due to resistance to hepcidin: high hepcidin concentrations in a family with C326S ferroportin mutation.

摘要: To the editor: The different genetic forms of hereditary hemochromatosis share as their pathogenic mechanisms deficiency or dysregulation hormone hepcidin defects involving receptor, ferroportin.1 Ferroportin is sole known cellular iron exporter in humans and present on enterocytes, macrophages, hepatocytes.2 Normally, cell-surface concentration ferroportin regulated by its interaction with hepcidin. Hepcidin binding triggers internalization degradation ferroportin-hepcidin complex, causing a decrease release into plasma.3 Mutations (SLC40A1) gene cause overload syndromes autosomal dominant transmission.4 mutations at least 2 distinct phenotypes, depending functional alteration protein. One subtype mutations, predominantly residues located putative cytoplasmic side transmembrane segments (eg, V162del, D157G, G80S, G490D), results loss export function.5 This leads to increased macrophage elevated serum ferritin, but normal transferrin saturation. phenotype, referred “ferroportin disease,” does not appear have significant morbidity. A ferroportin-related similar classical hemochromatosis, associated gain-of-function (eg N144D/T/H, Y64N, C326S/Y).6,7 In vitro evidence (companion manuscript, Fernandes et al8) indicates that these ferroportin's resistance effects N144D/T Y64N prevent hepcidin-ferroportin complex while C326S mutation completely ablates ferroportin. We previously reported most severe phenotype early age onset.6 In this study, we measured indices members family carrying heterozygous mutations.6 was competitive ELISA8 (Intrinsic LifeSciences, La Jolla, CA). The subjects had already been treated phlebotomy normalized stores, assessed saturation remained high (Table 1). patients (IIIC) has become iron-deficient due combined menstrual blood loss. Except for patient IIIC, all affected urinary concentrations upper limit range above These relatively levels are probably consequence patients' Only IIIC lower hepcidin, likely reflecting appropriate response deficiency. The despite depleted stores contrast low undetectable observed HFE, receptor 2, hemojuvelin hemochromatosis.9–11 Thus, our study provides first direct can be caused absence mutant excessive activity duodenal enterocytes unrestrained dietary absorption, which would account early-onset systemic seen juvenile hemochromatosis. Our findings support concept parenchymal iron-loading either effect