The Molecular Genetics of Haemochromatosis

The molecular basis of haemochromatosis has proved more complex than expected. After the 1996 identification of the main causative gene HFE and confirmation that most patients were homozygous for the founder C282Y mutation, it became clear that some families were linked to rarer conditions, first named 'non-HFE haemochromatosis'. The genetics of these less common forms was intensively studied between 2000 and 2004, leading to the recognition of haemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin-related haemochromatosis, and opening the way for novel hypotheses such as those related to digenic modes of inheritance or the involvement of modifier genes. Molecular studies of rare haemochromatosis disorders have contributed to our understanding of iron homeostasis. In turn, recent findings from studies of knockout mice and functional studies have confirmed that HAMP plays a central role in mobilization of iron, shown that HFE, TFR2 and HJV modulate HAMP production according to the body's iron status, and demonstrated that HAMP negatively regulates cellular iron efflux by affecting the ferroportin cell surface availability. These data shed new light on the pathophysiology of all types of haemochromatosis, and offer novel opportunities to comment on phenotypic differences and distinguish mutations.