Hereditary hemochromatosis since discovery of the HFE gene

Background: Hereditary hemochromatosis is an inherited disorder of iron met abolism that is characterized by excessive iron deposition in major organs of the body. Chronic increased iron absorption leads to multiorgan dysfunct ion. Since the discovery of the gene responsible for the majority of cases, research has progressed rapidly to identify the gene product, the effects of mutations, and the implications for different populations. The protein p roduct of the HFE gene is a transmembrane glycoprotein, termed HFE, that mo dulates iron uptake. Mutations in the HFE protein compromise its function a nd produce disease symptoms. Two mutations, C282Y and H63D, have been linke d to the majority of disease cases. Approach: We reviewed the recent literature for the molecular basis of here ditary hemochromatosis. Genotypic information was combined with biochemical and clinical phenotypic information to achieve a better understanding of t he disease mechanism. Content: This review provides a comprehensive discussion of known mutations in the HFE gene and their phenotypic expression. Diagnostic criteria using molecular genetic techniques in conjunction with traditional biochemical t ests are provided. Current methods and limitations of molecular testing are examined in detail. A strategy for population screening and an algorithm f or diagnosis that incorporates molecular testing are presented. Treatment b y therapeutic phlebotomy and the use of blood obtained from hemochromatosis patients are discussed. Summary: Although the disease mechanism has not been completely elucidated, phenotypic and penetrance data are becoming available. Controversy still e xists concerning the role of genetic testing in diagnosis and population sc reening. (C) 2001 American Association for Clinical Chemistry.