title: Resistance of ferroportin to hepcidin binding causes exocrine pancreatic failure and fatal iron overload.
abstract: The regulatory axis between the iron hormone hepcidin and its receptor, the iron exporter ferroportin (FPN), is central to iron homeostasis. Mutations preventing hepcidin-mediated degradation of FPN cause systemic iron overload. We have introduced a point mutation (C326S) into the murine Fpn locus, resembling human hereditary hemochromatosis type 4, including elevated plasma iron and ferritin levels, high transferrin saturation, hepatic iron overload, and iron depletion of duodenal enterocytes and reticuloendothelial macrophages. Unlike other mouse models of iron overload, homozygous C326S mice die between 7 and 14 months of age. Pancreatic acinar cells display marked iron accumulation, oxidative damage and degeneration, associated with failure of the exocrine pancreas and severe body weight loss. Rescue experiments reveal iron overload and exocrine pancreatic failure as leading causes of death. This work uncovers the critical importance of the hepcidin-ferroportin regulatory axis for life and unveils the sensitivity of the exocrine pancreas to iron overload.
authors.affiliation: Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany; Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany.
authors.forename: Sandro
authors.initials: S
authors.lastname: Altamura
authors.affiliation: Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany; Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Kessler
authors.affiliation: Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.affiliation: Medical Faculty Mannheim, 68167 Mannheim, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.affiliation: Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany; European Molecular Biology Laboratory, 69120 Heidelberg, Germany.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Hentze
authors.affiliation: European Molecular Biology Laboratory, 69120 Heidelberg, Germany. Electronic address: galy@embl.de.
authors.forename: Bruno
authors.initials: B
authors.lastname: Galy
authors.affiliation: Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany; Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany. Electronic address: martina.muckenthaler@med.uni-heidelberg.de.
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
mesh_terms: D061354:Acinar Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D027682:Cation Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D064451:Hepcidins / Q000737:chemistry / Q000378:metabolism*; D006720:Homozygote; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D010182:Pancreatic Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D064451:Hepcidins; D000098742:Ferroportin; D007501:Iron