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Genetics of hereditary hemochromatosis

Stanley L Schrier, MD
Bruce R Bacon, MD
Section Editors
William C Mentzer, MD
Benjamin A Raby, MD, MPH
Deputy Editor
Jennifer S Tirnauer, MD


Hereditary hemochromatosis (HH), also called genetic hemochromatosis, is a genetically determined disorder in which mutations of certain genes involved in iron metabolism can cause increased intestinal iron absorption. The genetics of HH and our expanding understanding of the function of both the normal and mutant proteins involved in iron metabolism will be reviewed here.

The clinical manifestations of this disorder (and of other forms of iron overload) are related to iron deposition in tissues, such as the liver, pancreas, and heart. These manifestations, and our approach to the diagnosis of HH in patients with these findings, are presented separately. (See "Approach to the patient with suspected iron overload" and "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

Screening in asymptomatic individuals and management of HH are also presented separately. (See "Screening for hereditary hemochromatosis" and "Management of patients with hereditary hemochromatosis".)


Since 1976, it has been known that the gene for HH is closely linked to the HLA-A3 locus, placing the gene on the short arm of chromosome 6 [1]. Previously, HLA typing had been useful in family studies [2]. However, with the availability of HFE mutation analysis, such studies are no longer relevant [3-5].

The gene for HH was identified and described in 1996 [6]. Using a positional cloning technique, a novel MHC class 1-type gene, originally called HLA-H and now termed HFE (for hereditary Fe [iron]), was found containing two missense mutations. One of these mutations results in a cysteine-to-tyrosine substitution at amino acid 282 (C282Y). Of 178 patients from 32 different medical centers around the United States, the C282Y mutation was found to be homozygous in 83 percent of patients with HH.

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Literature review current through: Sep 2017. | This topic last updated: Jul 20, 2017.
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