How mutant HFE causes hereditary hemochromatosis.

In this issue of Blood, Wu et al describe the molecular function of HFE, the gene most commonly mutated in hereditary hemochromatosis (HH). HH is the most frequent genetic disorder of the Western world. The authors show that HFE prevents ubiquitination and proteasomal degradation of bone-morphogenetic protein (BMP) receptor type I (Alk3), thereby increasing expression of this receptor on the cell surface of hepatocytes. As a consequence, transcription of the iron-hormone hepcidin is activated.