TY - JOUR
T1 - Clinical, pathological, and molecular correlates in ferroportin disease
T2 - A study of two novel mutations
AU - Girelli, Domenico
AU - De Domenico, Ivana
AU - Bozzini, Claudia
AU - Campostrini, Natascia
AU - Busti, Fabiana
AU - Castagna, Annalisa
AU - Soriani, Nadia
AU - Cremonesi, Laura
AU - Ferrari, Maurizio
AU - Colombari, Romano
AU - McVey Ward, Diane
AU - Kaplan, Jerry
AU - Corrocher, Roberto
PY - 2008/10
Y1 - 2008/10
N2 - 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.
AB - 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.
KW - Ferroportin
KW - Hemochromatosis
KW - Hepcidin
KW - Iron overload
KW - Zebrafish
UR - http://www.scopus.com/inward/record.url?scp=50549095186&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=50549095186&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2008.05.028
DO - 10.1016/j.jhep.2008.05.028
M3 - Article
C2 - 18713659
AN - SCOPUS:50549095186
VL - 49
SP - 664
EP - 671
JO - Journal of Hepatology
JF - Journal of Hepatology
SN - 0168-8278
IS - 4
ER -