Advertisement

Iron metabolism and related genetic diseases: A cleared land, keeping mysteries

  • Pierre Brissot
    Correspondence
    Corresponding authors. Addresses: Hepatology – Faculty of Medicine, 2 Avenue Pr. Léon Bernard, 35043, Rennes, France. Tel.: +33 0223235469 (P. Brissot) or Inserm U-991-Pontchaillou Hospital, 2 Rue Henri Le Guilloux- 35033-Rennes, France. Tel.: +33 0223233865 (O. Loréal).
    Affiliations
    Inserm-UMR 991, National Center of Reference for Rare Iron Overload Diseases, University Hospital Pontchaillou, Faculty of Medicine, Rennes, France
    Search for articles by this author
  • Olivier Loréal
    Correspondence
    Corresponding authors. Addresses: Hepatology – Faculty of Medicine, 2 Avenue Pr. Léon Bernard, 35043, Rennes, France. Tel.: +33 0223235469 (P. Brissot) or Inserm U-991-Pontchaillou Hospital, 2 Rue Henri Le Guilloux- 35033-Rennes, France. Tel.: +33 0223233865 (O. Loréal).
    Affiliations
    Inserm-UMR 991, National Center of Reference for Rare Iron Overload Diseases, University Hospital Pontchaillou, Faculty of Medicine, Rennes, France
    Search for articles by this author
Published:November 17, 2015DOI:https://doi.org/10.1016/j.jhep.2015.11.009

      Summary

      Body iron has a very close relationship with the liver. Physiologically, the liver synthesizes transferrin, in charge of blood iron transport; ceruloplasmin, acting through its ferroxidase activity; and hepcidin, the master regulator of systemic iron. It also stores iron inside ferritin and serves as an iron reservoir, both protecting the cell from free iron toxicity and ensuring iron delivery to the body whenever needed. The liver is first in line for receiving iron from the gut and the spleen, and is, therefore, highly exposed to iron overload when plasma iron is in excess, especially through its high affinity for plasma non-transferrin bound iron. The liver is strongly involved when iron excess is related either to hepcidin deficiency, as in HFE, hemojuvelin, hepcidin, and transferrin receptor 2 related haemochromatosis, or to hepcidin resistance, as in type B ferroportin disease. It is less involved in the usual (type A) form of ferroportin disease which targets primarily the macrophagic system. Hereditary aceruloplasminemia raises important pathophysiological issues in light of its peculiar organ iron distribution.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Hepatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Meynard D.
        • Babitt J.L.
        • Lin H.Y.
        The liver: conductor of systemic iron balance.
        Blood. 2014; 123: 168-176
        • Andrews N.C.
        • Schmidt P.J.
        Iron homeostasis.
        Annu Rev Physiol. 2007; 69: 69-85
        • Lane D.J.
        • Merlot A.M.
        • Huang M.L.
        • Bae D.H.
        • Jansson P.J.
        • Sahni S.
        • et al.
        Cellular iron uptake, trafficking and metabolism: key molecules and mechanisms and their roles in disease.
        Biochim Biophys Acta. 2015; 1853: 1130-1144
        • Brissot P.
        • Cavey T.
        • Troadec M.B.
        • Ropert M.
        • Loréal O.
        Métabolisme du fer.
        EMC Endocrinol Métabol. 2015; : 1-11
        • Chiabrando D.
        • Vinchi F.
        • Fiorito V.
        • Mercurio S.
        • Tolosano E.
        Heme in pathophysiology: a matter of scavenging, metabolism and trafficking across cell membranes.
        Front Pharmacol. 2014; 5: 61
        • Lawen A.
        • Lane D.J.
        Mammalian iron homeostasis in health and disease: uptake, storage, transport, and molecular mechanisms of action.
        Antioxid Redox Signal. 2013; 18: 2473-2507
        • Davidsson L.
        Approaches to improve iron bioavailability from complementary foods.
        J Nutr. 2003; 133: 1560S-1562S
        • Halfdanarson T.R.
        • Litzow M.R.
        • Murray J.A.
        Hematologic manifestations of celiac disease.
        Blood. 2007; 109: 412-421
        • Hershko C.
        • Graham G.
        • Bates G.W.
        • Rachmilewitz E.A.
        Non-specific serum iron in thalassaemia: an abnormal serum iron fraction of potential toxicity.
        Br J Haematol. 1978; 40: 255-263
        • Brissot P.
        • Wright T.L.
        • Ma W.L.
        • Weisiger R.A.
        Efficient clearance of non-transferrin-bound iron by rat liver. Implications for hepatic iron loading in iron overload states.
        J Clin Invest. 1985; 76: 1463-1470
        • Craven C.M.
        • Alexander J.
        • Eldridge M.
        • Kushner J.P.
        • Bernstein S.
        • Kaplan J.
        Tissue distribution and clearance kinetics of non-transferrin-bound iron in the hypotransferrinemic mouse: a rodent model for hemochromatosis.
        Proc Natl Acad Sci U S A. 1987; 84: 3457-3461
        • Liuzzi J.P.
        • Aydemir F.
        • Nam H.
        • Knutson M.D.
        • Cousins R.J.
        Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells.
        Proc Natl Acad Sci U S A. 2006; 103: 13612-13617
        • Jenkitkasemwong S.
        • Wang C.Y.
        • Coffey R.
        • Zhang W.
        • Chan A.
        • Biel T.
        • et al.
        SLC39A14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis.
        Cell Metab. 2015; 22: 138-150
        • Hider R.C.
        Nature of nontransferrin-bound iron.
        Eur J Clin Invest. 2002; 32: 50-54
        • Brissot P.
        • Ropert M.
        • Le Lan C.
        • Loreal O.
        Non-transferrin bound iron: a key role in iron overload and iron toxicity.
        Biochim Biophys Acta. 2012; 1820: 403-410
        • Esposito B.P.
        • Breuer W.
        • Sirankapracha P.
        • Pootrakul P.
        • Hershko C.
        • Cabantchik Z.I.
        Labile plasma iron in iron overload: redox activity and susceptibility to chelation.
        Blood. 2003; 102: 2670-2677
        • Cabantchik Z.I.
        • Breuer W.
        • Zanninelli G.
        • Cianciulli P.
        LPI-labile plasma iron in iron overload.
        Best Pract Res Clin Haematol. 2005; 18: 277-287
        • Le Lan C.
        • Loreal O.
        • Cohen T.
        • Ropert M.
        • Glickstein H.
        • Laine F.
        • et al.
        Redox active plasma iron in C282Y/C282Y hemochromatosis.
        Blood. 2005; 105: 4527-4531
        • Cabantchik Z.I.
        Labile iron in cells and body fluids: physiology, pathology, and pharmacology.
        Front Pharmacol. 2014; 5: 45
        • McKie A.T.
        • Barrow D.
        • Latunde-Dada G.O.
        • Rolfs A.
        • Sager G.
        • Mudaly E.
        • et al.
        An iron-regulated ferric reductase associated with the absorption of dietary iron.
        Science. 2001; 291: 1755-1759
        • Ohgami R.S.
        • Campagna D.R.
        • McDonald A.
        • Fleming M.D.
        The Steap proteins are metalloreductases.
        Blood. 2006; 108: 1388-1394
        • Mukhopadhyay C.K.
        • Attieh Z.K.
        • Fox P.L.
        Role of ceruloplasmin in cellular iron uptake.
        Science. 1998; 279: 714-717
        • Vulpe C.D.
        • Kuo Y.M.
        • Murphy T.L.
        • Cowley L.
        • Askwith C.
        • Libina N.
        • et al.
        Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse.
        Nat Genet. 1999; 21: 195-199
        • Arosio P.
        • Ingrassia R.
        • Cavadini P.
        Ferritins: a family of molecules for iron storage, antioxidation and more.
        Biochim Biophys Acta. 2009; 1790: 589-599
        • Lane D.J.
        • Richardson D.R.
        The active role of vitamin C in mammalian iron metabolism: much more than just enhanced iron absorption!.
        Free Radic Biol Med. 2014; 75: 69-83
        • Jomova K.
        • Valko M.
        Advances in metal-induced oxidative stress and human disease.
        Toxicology. 2011; 283: 65-87
        • Brissot P.
        • Deugnier Y.
        • Guyader D.
        • Zanninelli G.
        • Loreal O.
        • Moirand R.
        • et al.
        Iron overload and the biliary route.
        Adv Exp Med Biol. 1994; 356: 277-283
        • Brissot P.
        • Bardou-Jacquet E.
        • Jouanolle A.M.
        • Loreal O.
        Iron disorders of genetic origin: a changing world.
        Trends Mol Med. 2011; 17: 707-713
        • Tolosano E.
        Increasing serum transferrin to reduce tissue iron overload due to ineffective erythropoiesis.
        Haematologica. 2015; 100: 565-566
        • Fishbane S.
        • Mathew A.
        • Vaziri N.D.
        Iron toxicity: relevance for dialysis patients.
        Nephrol Dial Transplant. 2014; 29: 255-259
        • Porter J.B.
        • Garbowski M.
        The pathophysiology of transfusional iron overload.
        Hematol Oncol Clin North Am. 2014; 28 (vi): 683-701
        • Crichton R.R.
        Iron metabolism: from molecular mechanisms to clinical consequences.
        Wiley edits, 2009
        • Pigeon C.
        • Ilyin G.
        • Courselaud B.
        • Leroyer P.
        • Turlin B.
        • Brissot P.
        • et al.
        A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload.
        J Biol Chem. 2001; 276: 7811-7819
        • Nicolas G.
        • Bennoun M.
        • Devaux I.
        • Beaumont C.
        • Grandchamp B.
        • Kahn A.
        • et al.
        Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice.
        Proc Natl Acad Sci U S A. 2001; 98: 8780-8785
        • Loreal O.
        • Cavey T.
        • Bardou-Jacquet E.
        • Guggenbuhl P.
        • Ropert M.
        • Brissot P.
        Iron, hepcidin, and the metal connection.
        Front Pharmacol. 2014; 5: 128
        • Ganz T.
        Systemic iron homeostasis.
        Physiol Rev. 2013; 93: 1721-1741
        • Zhao N.
        • Zhang A.S.
        • Enns C.A.
        Iron regulation by hepcidin.
        J Clin Invest. 2013; 123: 2337-2343
        • Verga Falzacappa M.V.
        • Casanovas G.
        • Hentze M.W.
        • Muckenthaler M.U.
        A bone morphogenetic protein (BMP)-responsive element in the hepcidin promoter controls HFE2-mediated hepatic hepcidin expression and its response to IL-6 in cultured cells.
        J Mol Med (Berl). 2008; 86: 531-540
        • Ramey G.
        • Deschemin J.C.
        • Vaulont S.
        Cross-talk between the mitogen activated protein kinase and bone morphogenetic protein/hemojuvelin pathways is required for the induction of hepcidin by holotransferrin in primary mouse hepatocytes.
        Haematologica. 2009; 94: 765-772
        • Hentze M.W.
        • Muckenthaler M.U.
        • Galy B.
        • Camaschella C.
        Two to tango: regulation of Mammalian iron metabolism.
        Cell. 2010; 142: 24-38
        • Wu X.G.
        • Wang Y.
        • Wu Q.
        • Cheng W.H.
        • Liu W.
        • Zhao Y.
        • et al.
        HFE interacts with the BMP type I receptor ALK3 to regulate hepcidin expression.
        Blood. 2014; 124: 1335-1343
        • Corradini E.
        • Meynard D.
        • Wu Q.
        • Chen S.
        • Ventura P.
        • Pietrangelo A.
        • et al.
        Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice.
        Hepatology. 2011; 54: 273-284
        • Ramos E.
        • Kautz L.
        • Rodriguez R.
        • Hansen M.
        • Gabayan V.
        • Ginzburg Y.
        • et al.
        Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice.
        Hepatology. 2011; 53: 1333-1341
        • Zhang A.S.
        • Anderson S.A.
        • Wang J.
        • Yang F.
        • DeMaster K.
        • Ahmed R.
        • et al.
        Suppression of hepatic hepcidin expression in response to acute iron deprivation is associated with an increase of matriptase-2 protein.
        Blood. 2011; 117: 1687-1699
        • McKie A.T.
        • Marciani P.
        • Rolfs A.
        • Brennan K.
        • Wehr K.
        • Barrow D.
        • et al.
        A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation.
        Mol Cell. 2000; 5: 299-309
        • De Domenico I.
        • Ward D.M.
        • Nemeth E.
        • Vaughn M.B.
        • Musci G.
        • Ganz T.
        • et al.
        The molecular basis of ferroportin-linked hemochromatosis.
        Proc Natl Acad Sci U S A. 2005; 102: 8955-8960
        • Brasse-Lagnel C.
        • Karim Z.
        • Letteron P.
        • Bekri S.
        • Bado A.
        • Beaumont C.
        Intestinal DMT1 cotransporter is down-regulated by hepcidin via proteasome internalization and degradation.
        Gastroenterology. 2011; 140: e1261
        • Nemeth E.
        • Rivera S.
        • Gabayan V.
        • Keller C.
        • Taudorf S.
        • Pedersen B.K.
        • et al.
        IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin.
        J Clin Invest. 2004; 113: 1271-1276
        • Armitage A.E.
        • Eddowes L.A.
        • Gileadi U.
        • Cole S.
        • Spottiswoode N.
        • Selvakumar T.A.
        • et al.
        Hepcidin regulation by innate immune and infectious stimuli.
        Blood. 2011; 118: 4129-4139
        • Besson-Fournier C.
        • Latour C.
        • Kautz L.
        • Bertrand J.
        • Ganz T.
        • Roth M.P.
        • et al.
        Induction of activin B by inflammatory stimuli up-regulates expression of the iron-regulatory peptide hepcidin through Smad1/5/8 signaling.
        Blood. 2012; 120: 431-439
        • Kautz L.
        • Jung G.
        • Valore E.V.
        • Rivella S.
        • Nemeth E.
        • Ganz T.
        Identification of erythroferrone as an erythroid regulator of iron metabolism.
        Nat Genet. 2014; 46: 678-684
        • Kautz L.
        • Nemeth E.
        Molecular liaisons between erythropoiesis and iron metabolism.
        Blood. 2014; 124: 479-482
        • Detivaud L.
        • Nemeth E.
        • Boudjema K.
        • Turlin B.
        • Troadec M.B.
        • Leroyer P.
        • et al.
        Hepcidin levels in humans are correlated with hepatic iron stores, hemoglobin levels, and hepatic function.
        Blood. 2005; 106: 746-748
        • Maras J.S.
        • Maiwall R.
        • Harsha H.C.
        • Das S.
        • Hussain M.S.
        • Kumar C.
        • et al.
        Dysregulated iron homeostasis is strongly associated with multiorgan failure and early mortality in acute-on-chronic liver failure.
        Hepatology. 2015; 61: 1306-1320
        • Zhang D.L.
        • Ghosh M.C.
        • Rouault T.A.
        The physiological functions of iron regulatory proteins in iron homeostasis – an update.
        Front Pharmacol. 2014; 5: 124
        • Wilkinson N.
        • Pantopoulos K.
        The IRP/IRE system in vivo: insights from mouse models.
        Front Pharmacol. 2014; 5: 176
        • Shayeghi M.
        • Latunde-Dada G.O.
        • Oakhill J.S.
        • Laftah A.H.
        • Takeuchi K.
        • Halliday N.
        • et al.
        Identification of an intestinal heme transporter.
        Cell. 2005; 122: 789-801
        • Qiu A.
        • Jansen M.
        • Sakaris A.
        • Min S.H.
        • Chattopadhyay S.
        • Tsai E.
        • et al.
        Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption.
        Cell. 2006; 127: 917-928
        • Evans R.W.
        • Rafique R.
        • Zarea A.
        • Rapisarda C.
        • Cammack R.
        • Evans P.J.
        • et al.
        Nature of non-transferrin-bound iron: studies on iron citrate complexes and thalassemic sera.
        J Biol Inorg Chem. 2008; 13: 57-74
        • Richardson D.R.
        • Lane D.J.
        • Becker E.M.
        • Huang M.L.
        • Whitnall M.
        • Suryo Rahmanto Y.
        • et al.
        Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol.
        Proc Natl Acad Sci U S A. 2010; 107: 10775-10782
        • Shi H.
        • Bencze K.Z.
        • Stemmler T.L.
        • Philpott C.C.
        A cytosolic iron chaperone that delivers iron to ferritin.
        Science. 2008; 320: 1207-1210
        • Leidgens S.
        • Bullough K.Z.
        • Shi H.
        • Li F.
        • Shakoury-Elizeh M.
        • Yabe T.
        • et al.
        Each member of the poly-r(C)-binding protein 1 (PCBP) family exhibits iron chaperone activity toward ferritin.
        J Biol Chem. 2013; 288: 17791-17802
        • Gkouvatsos K.
        • Papanikolaou G.
        • Pantopoulos K.
        Regulation of iron transport and the role of transferrin.
        Biochim Biophys Acta. 2012; 1820: 188-202
        • Porto G.
        • De Sousa M.
        Iron overload and immunity.
        World J Gastroenterol. 2007; 13: 4707-4715
        • Cohen L.A.
        • Gutierrez L.
        • Weiss A.
        • Leichtmann-Bardoogo Y.
        • Zhang D.L.
        • Crooks D.R.
        • et al.
        Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway.
        Blood. 2010; 116: 1574-1584
        • Brissot P.
        • Bardou-Jacquet E.
        • Jouanolle A.M.
        • Loreal O.
        Iron disorders of genetic origin: a changing world.
        Trends Mol Med. 2011; 17: 707-713
        • Bardou-Jacquet E.
        • Ben Ali Z.
        • Beaumont-Epinette M.P.
        • Loreal O.
        • Jouanolle A.M.
        • Brissot P.
        Non-HFE hemochromatosis: pathophysiological and diagnostic aspects.
        Clin Res Hepatol Gastroenterol. 2013;
        • Drakesmith H.
        • Schimanski L.M.
        • Ormerod E.
        • Merryweather-Clarke A.T.
        • Viprakasit V.
        • Edwards J.P.
        • et al.
        Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin.
        Blood. 2005; 106: 1092-1097
        • Sham R.L.
        • Phatak P.D.
        • West C.
        • Lee P.
        • Andrews C.
        • Beutler E.
        Autosomal dominant hereditary hemochromatosis associated with a novel ferroportin mutation and unique clinical features.
        Blood Cells Mol Dis. 2005; 34: 157-161
        • Sham R.L.
        • Phatak P.D.
        • Nemeth E.
        • Ganz T.
        Hereditary hemochromatosis due to resistance to hepcidin: high hepcidin concentrations in a family with C326S ferroportin mutation.
        Blood. 2009; 114: 493-494
        • Fernandes A.
        • Preza G.C.
        • Phung Y.
        • De Domenico I.
        • Kaplan J.
        • Ganz T.
        • et al.
        The molecular basis of hepcidin-resistant hereditary hemochromatosis.
        Blood. 2009; 114: 437-443
        • Pietrangelo A.
        Genetics, Genetic Testing and Management of Hemochromatosis: 15 years since hepcidin.
        Gastroenterology. 2015;
        • Bardou-Jacquet E.
        • Philip J.
        • Lorho R.
        • Ropert M.
        • Latournerie M.
        • Houssel-Debry P.
        • Guyader D.
        • et al.
        Liver transplantation normalizes serum hepcidin level and cures iron metabolism alterations in HFE hemochromatosis.
        Hepatology. 2013;
        • Gandon Y.
        • Olivie D.
        • Guyader D.
        • Aube C.
        • Oberti F.
        • Sebille V.
        • et al.
        Non-invasive assessment of hepatic iron stores by MRI.
        Lancet. 2004; 363: 357-362
        • St Pierre T.G.
        • Clark P.R.
        • Chua-anusorn W.
        • Fleming A.J.
        • Jeffrey G.P.
        • Olynyk J.K.
        • et al.
        Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance.
        Blood. 2005; 105: 855-861
        • Wood J.C.
        Impact of iron assessment by MRI.
        Hematology Am Soc Hematol Educ Program. 2011; 2011: 443-450
        • Deugnier Y.
        • Turlin B.
        Pathology of hepatic iron overload.
        Semin Liver Dis. 2011; 31: 260-271
        • HAS
        French recommendations for management of HFE hemochromatosis.
        Haute Autorité de Santé, 2005 (www.has-sante.fr)
        • Brissot P.
        • Ball S.
        • Rofail D.
        • Cannon H.
        • Jin V.W.
        Hereditary hemochromatosis: patient experiences of the disease and phlebotomy treatment.
        Transfusion. 2011; 51: 1331-1338
        • Porto G.
        • Brissot P.
        • Swinkels D.W.
        • Zoller H.
        • Kamarainen O.
        • Patton S.
        • Alonso I.
        • et al.
        EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH).
        Eur J Hum Genet. 2015;
        • Allen K.J.
        • Gurrin L.C.
        • Constantine C.C.
        • Osborne N.J.
        • Delatycki M.B.
        • Nicoll A.J.
        • et al.
        Iron-overload-related disease in HFE hereditary hemochromatosis.
        N Engl J Med. 2008; 358: 221-230
        • Fletcher L.M.
        • Powell L.W.
        Hemochromatosis and alcoholic liver disease.
        Alcohol. 2003; 30: 131-136
        • Desgrippes R.
        • Laine F.
        • Morcet J.
        • Perrin M.
        • Manet G.
        • Jezequel C.
        • et al.
        Decreased iron burden in overweight C282Y homozygous women: Putative role of increased hepcidin production.
        Hepatology. 2013; 57: 1784-1792
        • Island M.L.
        • Jouanolle A.M.
        • Mosser A.
        • Deugnier Y.
        • David V.
        • Brissot P.
        • et al.
        A new mutation in the hepcidin promoter impairs its BMP response and contributes to a severe phenotype in HFE related hemochromatosis.
        Haematologica. 2009; 94: 720-724
        • Valenti L.
        • Fracanzani A.L.
        • Rametta R.
        • Fraquelli M.
        • Soverini G.
        • Pelusi S.
        • et al.
        Effect of the A736V TMPRSS6 polymorphism on the penetrance and clinical expression of hereditary hemochromatosis.
        J Hepatol. 2012; 57: 1319-1325
        • McLaren C.E.
        • Emond M.J.
        • Subramaniam V.N.
        • Phatak P.D.
        • Barton J.C.
        • Adams P.C.
        • et al.
        Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload.
        Hepatology. 2015; 62: 429-439
        • de Tayrac M.
        • Roth M.P.
        • Jouanolle A.M.
        • Coppin H.
        • le Gac G.
        • Piperno A.
        • et al.
        Genome-wide association study identifies TF as a significant modifier gene of iron metabolism in HFE hemochromatosis.
        J Hepatol. 2015; 62: 664-672
        • Milet J.
        • Dehais V.
        • Bourgain C.
        • Jouanolle A.M.
        • Mosser A.
        • Perrin M.
        • et al.
        Common variants in the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE hemochromatosis penetrance.
        Am J Hum Genet. 2007; 81: 799-807
        • Fung E.
        • Nemeth E.
        Manipulation of the hepcidin pathway for therapeutic purposes.
        Haematologica. 2013; 98: 1667-1676
        • Njajou O.T.
        • Vaessen N.
        • Joosse M.
        • Berghuis B.
        • van Dongen J.W.
        • Breuning M.H.
        • et al.
        A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis.
        Nat Genet. 2001; 28: 213-214
        • Montosi G.
        • Donovan A.
        • Totaro A.
        • Garuti C.
        • Pignatti E.
        • Cassanelli S.
        • et al.
        Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene.
        J Clin Invest. 2001; 108: 619-623
        • Pietrangelo A.
        The ferroportin disease.
        Blood Cells Mol Dis. 2004; 32: 131-138
        • Miyajima H.
        Aceruloplasminemia.
        Neuropathology. 2015; 35: 83-90
        • Kono S.
        Aceruloplasminemia: an update.
        Int Rev Neurobiol. 2013; 110: 125-151
        • Finkenstedt A.
        • Wolf E.
        • Hofner E.
        • Gasser B.I.
        • Bosch S.
        • Bakry R.
        • et al.
        Hepatic but not brain iron is rapidly chelated by deferasirox in aceruloplasminemia due to a novel gene mutation.
        J Hepatol. 2010; 53: 1101-1107
        • Hattori A.
        • Tomosugi N.
        • Tatsumi Y.
        • Suzuki A.
        • Hayashi K.
        • Katano Y.
        • et al.
        Identification of a novel mutation in the HAMP gene that causes non-detectable hepcidin molecules in a Japanese male patient with juvenile hemochromatosis.
        Blood Cells Mol Dis. 2012; 48: 179-182
        • Tai M.
        • Matsuhashi N.
        • Ichii O.
        • Suzuki T.
        • Ejiri Y.
        • Kono S.
        • et al.
        Case of presymptomatic aceruloplasminemia treated with deferasirox.
        Hepatol Res. 2014; 44: 1253-1258
        • Rusticeanu M.
        • Zimmer V.
        • Schleithoff L.
        • Wonney K.
        • Viera J.
        • Zimmer A.
        • et al.
        Novel ceruloplasmin mutation causing aceruloplasminemia with hepatic iron overload and diabetes without neurological symptoms.
        Clin Genet. 2014; 85: 300-301
        • Loreal O.
        • Turlin B.
        • Pigeon C.
        • Moisan A.
        • Ropert M.
        • Morice P.
        • et al.
        Aceruloplasminemia: new clinical, pathophysiological and therapeutic insights.
        J Hepatol. 2002; 36: 851-856
        • De Domenico I.
        • Ward D.M.
        • di Patti M.C.
        • Jeong S.Y.
        • David S.
        • Musci G.
        • et al.
        Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin.
        EMBO J. 2007; 26: 2823-2831
        • Kaneko Y.
        • Miyajima H.
        • Piperno A.
        • Tomosugi N.
        • Hayashi H.
        • Morotomi N.
        • et al.
        Measurement of serum hepcidin-25 levels as a potential test for diagnosing hemochromatosis and related disorders.
        J Gastroenterol. 2010; 45: 1163-1171
        • Kono S.
        • Yoshida K.
        • Tomosugi N.
        • Terada T.
        • Hamaya Y.
        • Kanaoka S.
        • et al.
        Biological effects of mutant ceruloplasmin on hepcidin-mediated internalization of ferroportin.
        Biochim Biophys Acta. 2010; 1802: 968-975
        • Guo P.
        • Cui R.
        • Chang Y.Z.
        • Wu W.S.
        • Qian Z.M.
        • Yoshida K.
        • et al.
        Hepcidin, an antimicrobial peptide is downregulated in ceruloplasmin-deficient mice.
        Peptides. 2009; 30: 262-266
        • Aslan D.
        • Crain K.
        • Beutler E.
        A new case of human atransferrinemia with a previously undescribed mutation in the transferrin gene.
        Acta Haematol. 2007; 118: 244-247
        • Iolascon A.
        • Camaschella C.
        • Pospisilova D.
        • Piscopo C.
        • Tchernia G.
        • Beaumont C.
        Natural history of recessive inheritance of DMT1 mutations.
        J Pediatr. 2008; 152: 136-139
        • Bardou-Jacquet E.
        • Island M.L.
        • Jouanolle A.M.
        • Detivaud L.
        • Fatih N.
        • Ropert M.
        • et al.
        A novel N491S mutation in the human SLC11A2 gene impairs protein trafficking and in association with the G212V mutation leads to microcytic anemia and liver iron overload.
        Blood Cells Mol Dis. 2011; 47: 243-248
        • Ducamp S.
        • Kannengiesser C.
        • Touati M.
        • Garcon L.
        • Guerci-Bresler A.
        • Guichard J.F.
        • et al.
        Sideroblastic anemia: molecular analysis of the ALAS2 gene in a series of 29 probands and functional studies of 10 missense mutations.
        Hum Mutat. 2011; 32: 590-597
        • Guernsey D.L.
        • Jiang H.
        • Campagna D.R.
        • Evans S.C.
        • Ferguson M.
        • Kellogg M.D.
        • et al.
        Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia.
        Nat Genet. 2009; 41: 651-653
        • Bekri S.
        • Kispal G.
        • Lange H.
        • Fitzsimons E.
        • Tolmie J.
        • Lill R.
        • et al.
        Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation.
        Blood. 2000; 96: 3256-3264
        • Camaschella C.
        • Campanella A.
        • De Falco L.
        • Boschetto L.
        • Merlini R.
        • Silvestri L.
        • et al.
        The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload.
        Blood. 2007; 110: 1353-1358
        • Besur S.
        • Hou W.
        • Schmeltzer P.
        • Bonkovsky H.L.
        Clinically important features of porphyrin and heme metabolism and the porphyrias.
        Metabolites. 2014; 4: 977-1006
        • Finberg K.E.
        • Heeney M.M.
        • Campagna D.R.
        • Aydinok Y.
        • Pearson H.A.
        • Hartman K.R.
        • et al.
        Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA).
        Nat Genet. 2008; 40: 569-571
        • Heeney M.M.
        • Finberg K.E.
        Iron-refractory iron deficiency anemia (IRIDA).
        Hematol Oncol Clin North Am. 2014; 28 (v): 637-652
        • De Falco L.
        • Silvestri L.
        • Kannengiesser C.
        • Moran E.
        • Oudin C.
        • Rausa M.
        • et al.
        Functional and clinical impact of novel TMPRSS6 variants in iron-refractory iron-deficiency anemia patients and genotype-phenotype studies.
        Hum Mutat. 2014; 35: 1321-1329
        • Poggiali E.
        • Andreozzi F.
        • Nava I.
        • Consonni D.
        • Graziadei G.
        • Cappellini M.D.
        The role of TMPRSS6 polymorphisms in iron deficiency anemia partially responsive to oral iron treatment.
        Am J Hematol. 2015; 90: 306-309
        • Girelli D.
        • Corrocher R.
        • Bisceglia L.
        • Olivieri O.
        • De Franceschi L.
        • Zelante L.
        • et al.
        Molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome: a mutation in the iron-responsive element of ferritin L-subunit gene (the “Verona mutation”).
        Blood. 1995; 86: 4050-4053
        • Yin D.
        • Kulhalli V.
        • Walker A.P.
        Raised serum ferritin concentration in hereditary hyperferritinemia cataract syndrome is not a marker for iron overload.
        Hepatology. 2014; 59: 1204-1206
        • Bowes O.
        • Baxter K.
        • Elsey T.
        • Snead M.
        • Cox T.
        Hereditary hyperferritinaemia cataract syndrome.
        Lancet. 2014; 383: 1520
        • Kannengiesser C.
        • Jouanolle A.M.
        • Hetet G.
        • Mosser A.
        • Muzeau F.
        • Henry D.
        • et al.
        A new missense mutation in the L ferritin coding sequence associated with elevated levels of glycosylated ferritin in serum and absence of iron overload.
        Haematologica. 2009; 94: 335-339
        • Martelli A.
        • Puccio H.
        Dysregulation of cellular iron metabolism in Friedreich ataxia: from primary iron-sulfur cluster deficit to mitochondrial iron accumulation.
        Front Pharmacol. 2014; 5: 130