In 1996, researcher John Feder sealed the ongoing debate on the nature of hemochromatosis pathophysiology, when he discovered that there was a point mutation, Cys282Tyr, found in a region encoding the HLA-H protein later named the hemochromatosis protein or HFE (Feder 1996). This mutation was homozygous in 85% of patients he analyzed. (Feder 1996). Another common mutation found in this region was H63D (Feder 1996).
Table 1: Hemochromatosis variants; while HFE mutations are the most common mutations in other genes involved in the iron regulatory pathway also lead to hemochromatosis.
|80% cases worldwide
≤11% present phenotypically
often has a potentiator, e.g., hepatitis C
infection, thalassemia trait
|presents before age 30
equal sex ratio
|HFE3||mutation in TfR2
Tyr250 stop mutation
other mutations identified
mutation in ferroportin gene (SLC11A3)
African iron overload
Iron overload in
Immunohistochemistry experiments determined that the HFE protein was mainly found in the duodenum, specifically within the intestinal crypts indicating a role in the regulation of absorption of iron (Byrnes 2000). The study also found that the amount of HFE was slightly decreased in patients with hemochromatosis (Byrnes 2000).
HLA proteins typically serve as antigen presenting cells in the immune system however, HFE protein lacks two of the conserved tyrosine’s indicating a different function, however the function was unknown (Feder 1996). A few years later a preliminary crystal structure of the HFE protein was solved (Lebrón 1998). They found that the most prevalent mutation interrupted a disulfide bridge changing the proteins structure (Lebrón 1998). They also found that the HFE protein can bind to the transferrin receptor perhaps modifying affinity for Tf-fe to bind indicating a preliminary link to iron metabolism and that this binding occurred at a lower affinity with mutated HFE (Lebrón 1998). A year later the structure of the transferrin receptor was solved indicating it was a dimeric receptor and proposed a binding mechanism for TF-Fe to the receptor, which can be modified by pH (Lawrence 1999). This allows for the process of endocytosis, release of iron and exocytosis to occur and the receptor to maintain bonds to the transferrin molecule (Lawrence 1999). It was then was determined that HFE also binds Transferrin Receptor 2 (TFR2) and it was proposed that this served as a mechanism of sensing iron levels in the cell (Goswami 2006). HFE binds TFR1, however when there is a abundance of Tf-fe due to high levels of iron, HFE is displaced (Goswami 2006). Displaced HFE then binds to TFR2 and signals a cascade in which expression of hepcidin is induced (Goswami 2006).
Hepcidin is a small hormone produced by the liver, which regulates absorption of iron (Nemeth 2004). Hepcidin binds to ferroportin, a protein which facilitates the movement of iron from enterocytes, macrophages and hepatocytes to the plasma (Nemeth 2004). When hepcidin binds ferroportin it induces internalization and degradation of the protein (Nemeth 2004). The mechanisms by which hepcidin is regulated are complex and multifaceted and some have yet to be discovered. However, it has been shown that HFE regulates hepcidin expression through the BMP pathway (Wu 2014). HFE binds to ALK3, a type one BMP receptor, to promote cellular expression and inhibit ubiquitinization (Wu 2014). BMP6, Hemojuvelin (HJV) and ALK3 form a complex which induces phosphorylation of smad1/5/8 and thereby induces expression of hepcidin (Wu 2014).
HFE C282Y mutants are unable to induce the BMP pathway to express hepcidin as the mutated protein is unable to facilitate ALK3 transport to the cellular surface (Wu 2014). This causes the low levels of hepcidin that are a key factor in the disease process of hereditary hemochromatosis. Since levels of hepcidin are low, degradation of ferroportin is minimal and thus iron is continually absorbed from enterocytes and recycled from macrophages thereby creating the stores of iron seen in hereditary hemochromatosis. In addition, since mutated HFE does not bind TFR with high affinity, TFR continually binds TF-fe for uptake into the cell thereby increasing iron absorption which remains unregulated due to the lack of hepcidin.