title: The molecular pathogenesis of hereditary hemochromatosis.
abstract: Hereditary hemochromatosis is a genetic disorder of iron overload. Over the past 15 years, significant advances have been made in understanding the molecular pathogenesis of this disorder. First, genetic studies linked this disorder to mutations in several genes, including HFE, transferrin receptor 2 ( TFR2), hepcidin ( HAMP), ferroportin ( SLC40A1), and hemojuvelin ( HFE2). Recent progress has generated significant insight into the function of these molecules in systemic iron homeostasis, and has revealed that despite the genetic and phenotypic diversity of hereditary hemochromatosis, there are common pathogenic mechanisms underlying this disease. The common downstream mechanism of iron overload in hereditary hemochromatosis is abnormal regulation of the hepcidin-ferroportin axis, leading to a failure to prevent excess iron from entering the circulation. Recent data are starting to unravel the molecular mechanisms by which iron regulates hepcidin production, and has demonstrated a key role for the bone morphogenetic protein-hemojuvelin-SMAD signaling pathway in this process. Future studies will be needed to more fully understand the molecular mechanisms of iron sensing and the roles of HFE and TFR2 in this process. Here, the authors review the current state of knowledge on the molecular pathogenesis of hereditary hemochromatosis.
authors: Program in Membrane Biology, Division of Nephrology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Jodie L
authors: JL
authors: Babitt
authors: Herbert Y
authors: HY
authors: Lin
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism*; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D023181:Antimicrobial Cationic Peptides; D019485:Bone Morphogenetic Proteins; D027682:Cation Transport Proteins; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C103673:HFE protein, human; C481006:HJV protein, human; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011990:Receptors, Transferrin; D051785:Smad Proteins; C503640:TFR2 protein, human; D000098742:Ferroportin