How mutant HFE causes hereditary hemochromatosis
Wu et al describe the molecular function of HFE, the gene maximum typically mutated in hereditary hemochromatosis (HH). HH is the maximum common genetic disease of the Western world. The authors display that HFE prevents ubiquitination and proteasomal degradation of bone-morphogenetic protein (BMP) receptor type I (Alk3), thereby growing the expression of this receptor at the cell surface of hepatocytes. As a consequence, transcription of the iron-hormone hepcidin is activated.
Regulated protein-protein interactions amongst HFE, TfR2, HJV (proteins mutated in HH), BMP receptors, and BMP ligands play an essential function withinside the “sensing” of transferrin-certain Fe to manipulate hepcidin expression in hepatocytes. HFE binds to BMP receptor type I (Alk3) to prevent its ubiquitination and proteasomal degradation. As a result, the expression of ALK3 is multiplied at the cell surface, activating BMP/SMAD signaling and hepcidin transcription. Professional example via way of means of Tom Webster, Lineworks, Inc.
Hereditary hemochromatosis is probably deadly disease hallmarked via way of means of nutritional iron hyperabsorption, hyperferremia, and tissue iron overload. Complications consist of liver cirrhosis, cancer, diabetes, coronary heart failure, and arthritis that may be avoided via way of means of phlebotomy. All family studies recognized homozygous missense mutations of the HFE gene (C282Y) happening withinside the maximum common HH subtype.2 Wild-type HFE encodes a ubiquitously expressed essential histocompatibility complex class 1–like molecule (MHC-1). Of note, the aforementioned factor mutation inhibits binding of β2-microglobulin (β2M) and HFE cell-surface expression. Although HFE became determined nearly two decades ago, its molecular feature remained unknown.
Less common however clinically extra intense types of HH are resulting from mutations in hemojuvelin (HJV), transferrin receptor 2 (TfR2), or hepcidin (HAMP). Most probably, regulated protein/protein interactions a few of the membrane proteins HFE, TfR2, and HJV in hepatocytes combine indicators elicited through the awareness of iron-bound transferrin and hepatocytic iron stores, which in the end manage the expression of hepcidin. This iron hormone is secreted through hepatocytes and binds to the iron exporter ferroportin to suppress nutritional iron uptake and iron release from iron-recycling macrophages. These HH subtypes display unphysiologic low hepcidin levels, and is the reason improved nutritional iron uptake and systemic iron accumulation in those patients.