Clinical, pathological, and molecular correlates in ferroportin disease: A study of two novel mutations

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• 作者：Domenico Girelli ; Ivana De Domenico ; Claudia Bozzini ; Natascia Campostrini ; Fabiana Busti ; Annalisa Castagna ; Nadia Soriani ; Laura Cremonesi ; Maurizio Ferrari ; Romano Colombari ; Diane McVey Ward ; Jerr
• 关键词：Iron overload ; Ferroportin ; Hemochromatosis ; Hepcidin ; Zebrafish
• 刊名：Journal of Hepatology
• 出版年：2008
• 出版时间：October 2008
• 年：2008
• 卷：49
• 期：4
• 页码：664-671
• 全文大小：1633 K

文摘

Background/Aims

Clinico-pathological manifestations of ferroportin (Fpn) disease (FD) are heterogeneous, with some patients presenting with iron overload predominantly in macrophages (“M” phenotype), others predominantly in hepatocytes (“H” phenotype). This appears to reflect functional heterogeneity of Fpn mutants, with loss-of-function generally resulting in the M type.

Methods

Two unrelated probands with “non-HFE” hemochromatosis were screened for Fpn mutations. Mutants were functionally characterized by immunofluorescence microscopy, evaluation of their ability to bind hepcidin and export iron, and by expressing them in zebrafish.

Results

Two novel Fpn mutations were identified: I152F in patient-1, presenting with typical M phenotype; and L233P in patient-2, presenting with ambiguous features (massive overload in both macrophages and hepatocytes). Molecular studies suggested loss of function in both cases. The I152F, normally localized on cell membrane and internalized by hepcidin, showed a unique “primary” deficit of iron export capability. The L233P did not appropriately traffic to cell surface. Loss of function was confirmed by expressing both mutants in vivo in zebrafish, resulting in iron limited erythropoiesis. Clinical manifestations were likely enhanced in both patients by non-genetic factors (HCV, alcohol).

Conclusions

The combination of careful review of clinico-pathological data with molecular studies can yield compelling explanations for phenotype heterogeneity in FD.