What is the significance of the HFE (High Fe) gene?

From the Guidelines

The HFE gene is significant because it is associated with hereditary hemochromatosis, a genetic disorder that leads to excessive iron absorption and can cause life-threatening complications such as cirrhosis, hepatocellular cancer, diabetes, and heart disease 1.

Key Points

• The HFE gene is located on the short arm of chromosome 6 and has two main mutations: C282Y and H63D, which can lead to hereditary hemochromatosis 1.
• The C282Y mutation is the most common cause of hereditary hemochromatosis, and individuals who are homozygous for this mutation (C282Y/C282Y) have a high risk of developing the disease 1.
• The HFE gene plays a role in regulating iron metabolism, and mutations in this gene can lead to increased iron absorption and accumulation in the body 1.
• The HFE protein is physically associated with transferrin receptor-1 (TfR1) and may play a regulatory role in BMP6 signaling, which is important for iron metabolism 1.

Clinical Significance

• Hereditary hemochromatosis is a common genetic disorder in individuals of northern European origin, and early diagnosis and treatment can prevent complications and improve outcomes 1.
• The diagnosis of hereditary hemochromatosis typically involves genetic testing for the C282Y and H63D mutations, as well as measurement of iron levels and liver function tests 1.
• Treatment for hereditary hemochromatosis usually involves phlebotomy to remove excess iron from the body, and may also include dietary changes and other therapies to manage related conditions such as diabetes and heart disease 1.

From the Research

Significance of the HFE Gene

The HFE gene is significant in the regulation of iron homeostasis, and its mutations are associated with hereditary hemochromatosis, a common autosomal recessive genetic disorder of iron homeostasis 2, 3, 4, 5, 6.

Role in Iron Homeostasis

• The HFE gene encodes a major histocompatibility complex (MHC) class I-like protein that influences iron absorption by modulating the expression of hepcidin, the main controller of iron metabolism 5.
• The HFE protein binds to beta-2 microglobulin and is involved in the regulation of iron homeostasis, with mutations in this gene responsible for hereditary hemochromatosis 4, 6.
• The HFE gene knockout in mice produces a model of hereditary hemochromatosis, with increased iron absorption and progressive iron storage, resulting in damage to major organs in the body 6.

Expression and Regulation

• The HFE gene is highly expressed in the liver, and its promoter is regulated by liver-enriched transcription factors such as C/EBPalpha, as well as erythropoietic-specific GATA-1 and ubiquitous Sp1 transcription factors 2.
• The HFE gene has a complex regulation, with multiple cell types involved in iron metabolism, and its function is likely to be complex 3.

Mutations and Associated Iron Abnormalities

• Common HFE mutations account for ~90% of hemochromatosis phenotypes in whites of western European descent 5.
• The C282Y mutation in the HFE gene is found in nearly 90% of Caucasian hereditary hemochromatosis patients 6.
• HFE mutations are associated with increased iron absorption, elevated transferrin saturation, and serum ferritin levels, leading to iron overload and damage to major organs in the body 3, 4, 5, 6.