Hemojuvelin

Hemojuvelin (HJV/HFE2/RGMc) is a membrane protein that is responsible for the iron overload condition known as juvenile hemochromatosis, a severe form of hereditary hemochromatosis. Mutations in HJV are responsible for the vast majority of juvenile hemochromatosis patients. A small number of patients have mutations in the hepcidin (HAMP) gene. The gene was positionally cloned by Papanikolaou et al. in 2003. ^[1] Hemojuvelin is highly expressed in the liver, skeletal muscle and heart. One insight into the pathogenesis of juvenile hemochromatosis is that patients have low to undetectable urinary hepcidin levels, suggesting that hemojuvelin is a positive regulator of hepcidin, the central iron regulatory hormone. As a result, low hepcidin levels would result in increased intestinal iron absorption.

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For many years the signal transduction pathways that regulate systemic iron homeostasis have been unknown. However, an important study by Babitt et al. revealed that hemojuvelin is a bone morphogenetic protein (BMP) co-receptor and signals via the SMAD pathway to regulate hepcidin expression.^[2]

Mouse HJV knock-out models produced by Huang et al.^[3] and Niederkofler et al.^[4] confirmed that HJV is the gene responsible for juvenile hemochromatosis. Furthermore, the researchers showed that hepcidin levels in the liver are dramatically depressed.

Recent studies by Lin et al. suggest that soluble HJV may be a molecule that suppresses hepcidin expression.^[5]

Kuninger, et al., recently demonstrated that two classes of GPI-anchored and glycosylated RGMc molecules are targeted to the membrane and undergo distinct fates.^[6] (1) Full-length RGMc is released from the cell surface and accumulates in extracellular fluid, where its half-life exceeds 24 hours. By contrast, (2) the predominant membrane-associated isoform, a disulfide-linked heterodimer composed of N- and C-terminal fragments, is not found in the extracellular fluid, and is short-lived, as it disappears from the cell surface with a half-life of <3 hours after interruption of protein synthesis.

References

1. ^ Papanikolaou G, Samuels ME, Ludwig EH, et al (2004). "Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis". Nat. Genet. 36 (1): 77-82. doi:10.1038/ng1274. PMID 14647275.
2. ^ Babitt et al., Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression
3. ^ Huang et al., A mouse model of juvenile hemochromatosis
4. ^ Niederkofler et al., Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload
5. ^ Lin L, Goldberg YP, Ganz T (2005). "Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin". Blood 106 (8): 2884-9. doi:10.1182/blood-2005-05-1845. PMID 15998830.
6. ^ Kuninger D, Kuns-Hashimoto R, Kuzmickas R, Rotwein P. (2006). "Complex biosynthesis of the muscle-enriched iron regulator RGMc". J Cell Sci. 119 (16): 3273-83. PMID 16868025.

External links

• MeSH hemojuvelin,+human