As described earlier, hepcidin

is the central mediator of systemic iron homeostasis through its interaction with ferroportin and control of its cell surface expression. Mutations in hepcidin are very rare possibly because of the small size of the molecule and account for only a small proportion of patients with JH. Roetto et al. originally identified HAMP as the gene responsible for JH in two families http://www.selleckchem.com/products/bmn-673.html who did not have linkage to the chromosome 1q region.[38] To date, only 12 mutations have been reported in the hepcidin coding sequence or promoter region that have either been associated with JH or have been implicated as modifiers of the HFE-HH phenotype. Within the Asia-Pacific region, three mutations have been reported (Fig. 2). The C78T mutation was detected in a consanguineous family of Middle Eastern origin residing in Australia.[39] The R42Sfs mutation was reported in a consanguineous family from Pakistan; this frameshift mutation results in an abnormally elongated protein with complete disruption of the mature peptide

sequence.[34] Finally, the R75X mutation was recently reported in a Japanese patient with early onset hemochromatosis.[40] Interestingly, this mutation would be predicted to result in a truncated, 15 amino acid version of the mature peptide. However, no detectable hepcidin, either full length or truncated, was detected in the patient’s serum or urine, suggesting that there may have been defective processing or secretion of the mutant SPTLC1 peptide.[40]

Mutations in TFR2 as the cause of type 3 HH were first reported in 2000.[41] TFR2 is highly expressed in the hepatocytes FK866 of the liver where it has been implicated in the regulation of hepcidin. Cell surface TFR2 has the capacity to bind and internalize transferrin, although the affinity is significantly lower than that of TFR1.[42] Exactly how TFR2 in the hepatocyte regulates hepcidin is unclear. Some studies have suggested that TFR2 forms a complex with HFE and possibly HJV that is responsible for regulating hepcidin.[43-45] However, other reports suggest that a complex between HFE and TFR2 is not required for hepcidin regulation.[46, 47] While the mechanism of TFR2 action and the signal transduction to hepcidin remain unclear, reduced hepcidin relative to iron stores has been shown to be responsible for iron overload in patients with TFR2-HH.[48] While TFR2-HH was originally described as an adult-onset disease with similar age of presentation to HFE-HH, more recent evidence suggests that it has an earlier age of onset and a more severe clinical course.[49] Despite the earlier onset of TFR2-HH, the iron indices, tissue iron distribution, and clinical features are similar to HFE-HH. It now appears that TFR2-HH has a phenotypic severity that is intermediate between JH caused by HJV or HAMP mutations at one end of the spectrum and HFE-HH at the other. In contrast with JH, hypogonadism and cardiomyopathy are less common.