Name=hemochromatosis type 2 (juvenile)


Hemojuvelin (HJV/HFE2/RGMc) is a membrane-bound and soluble protein that is responsible for the iron overload condition known as juvenile hemochromatosis, a severe form of hereditary hemochromatosis.

Clinical significance

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. [cite journal |author=Papanikolaou G, Samuels ME, Ludwig EH, "et al" |title=Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis |journal=Nat. Genet. |volume=36 |issue=1 |pages=77–82 |year=2004 |pmid=14647275 |doi=10.1038/ng1274] Hemojuvelin is highly expressed in skeletal muscle and heart, and to a lesser extent in the liver. 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. Thus, HJV/RGMc appears to play a critical role in iron metabolism.


For many years the signal transduction pathways that regulate systemic iron homeostasis have been unknown. However, an important study by Babitt et al. suggested that hemojuvelin is a bone morphogenetic protein (BMP) co-receptor and signals via the SMAD pathway to regulate hepcidin expression. [ [http://www.nature.com/ng/journal/v38/n5/abs/ng1777.html Babitt et al., Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression] ] Associations with BMP2 and BMP4 have been described.cite journal |author=Zhang AS, Yang F, Meyer K, "et al" |title=Neogenin-mediated hemojuvelin shedding occurs after hemojuvelin traffics to the plamsa membrane |journal=J. Biol. Chem. |volume= |issue= |pages= |year=2008 |month=April |pmid=18445598 |doi=10.1074/jbc.M710527200 |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=18445598]

Mouse HJV knock-out models produced by Huang et al. [ [http://www.jci.org/cgi/content/full/115/8/2187?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=franklin+huang&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT Huang et al., A mouse model of juvenile hemochromatosis] ] and Niederkofler et al. [ [http://www.jci.org/cgi/content/full/115/8/2180?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=sylvia+arber&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT Niederkofler et al., Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload] ] 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 a soluble form of HJV may be a molecule that suppresses hepcidin expression. [cite journal |author=Lin L, Goldberg YP, Ganz T |title=Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin |journal=Blood |volume=106 |issue=8 |pages=2884–9 |year=2005 |pmid=15998830 |doi=10.1182/blood-2005-05-1845]

Molecules target to membrane

Kuninger, et al., recently demonstrated that two classes of GPI-anchored and glycosylated RGMc molecules are targeted to the membrane and undergo distinct fates. [cite journal |author=Kuninger D, Kuns-Hashimoto R, Kuzmickas R, Rotwein P. |title=Complex biosynthesis of the muscle-enriched iron regulator RGMc |journal=J Cell Sci. |volume=119 |issue=16 |pages=3273–83 |year=2006 |pmid=16868025 |doi=10.1242/jcs.03074 ]
* (1) Full-length RGMc is released from the cell surface and accumulates in extracellular fluid, where its half-life exceeds 24 hours. There appears to be two potential soluble isoforms and two membrane-associated isoforms.
* By contrast, (2) the predominant membrane-associated isoform, a disulfide-linked two-chain form 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.


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