The Molecular Pathogenesis of Hereditary Hemochromatosis

Jodie L Babitt; Herbert Y Lin

doi:10.1055/s-0031-1286059

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2011; 31(3): 280-292
DOI: 10.1055/s-0031-1286059

The Molecular Pathogenesis of Hereditary Hemochromatosis

Jodie L. Babitt¹ , Herbert Y. Lin¹

¹Program in Membrane Biology, Division of Nephrology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

Abstract

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.

KEYWORDS

Hemochromatosis - iron - hepcidin - bone morphogenetic protein - hemojuvelin - HFE - transferrin receptor 2 - ferroportin

Full Text

References

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Herbert Y LinM.D. Ph.D.

Program in Membrane Biology, Division of Nephrology, Center for Systems Biology, Massachusetts General Hospital

185 Cambridge Street, CPZN-8216, Boston, MA 02114

Email: Lin.herbert@mgh.harvard.edu