To date, over 20 non-synonymous, non-sense, frameshift, or splicing mutations have been reported. Some of these have only been observed in the heterozygous state and may

be simple polymorphisms. A large number have been reported in Italian HH patients, an area where HFE-HH accounts for only around 60% of cases.[1] In Asia, a region where the HFE C282Y mutation is rare, mutations in TFR2 have been associated with HH (Fig. 2). The AVAQ621-624del mutation, which was originally reported in Italy, has also been found in Japanese patients with HH[50] and more recently in a patient from Iran.[51] Other mutations that have been reported as the cause of type 3 HH in Asia are L490R and P555fsX561, both in Japanese patients[52] and R481H in a Taiwanese patient.[53] The R481H mutation was reported in a female with severe iron overload, but only in the heterozygous state; whether an additional http://www.selleckchem.com/products/GDC-0941.html mutation or other factors contributed to her iron overload are not clear.[53] The I238M variant of

TFR2 is relatively common and has been reported as a polymorphism.[54] It is particularly common in the Asian population (7% allele frequency, 1000 Genomes Project) and was found on the background of the L490R mutation in Japan.[52] Thus, although globally, TFR2-HH is rare, it may be a leading cause of HH in the Asia-Pacific region, in particular in Japan.[55] The ferroportin gene, SLC40A1, encodes a 62.5 kDa protein that localizes to the cell surface and is postulated to contain 12 transmembrane domains that form a channel through which iron is exported from cells.[56, 57] Mutations 上海皓元医药股份有限公司 in the ferroportin gene result in an autosomal dominant form of HH known as ferroportin Selleck Y-27632 disease. Ferroportin disease is usually an adult onset disease typically presenting in the 4th or 5th decade of life, with long-term iron loading leading to a broad

spectrum of outcomes depending on the disease-causing mutation. If the iron overload is untreated, clinical manifestations can include liver damage, including fibrosis and/or cirrhosis, diabetes mellitus, and arthritis. Further analysis of patients with ferroportin disease has revealed two phenotypically distinct subtypes. Most patients fall into the classical ferroportin disease phenotype that is characterized by elevated serum ferritin but low to normal or only mildly elevated transferrin saturation. Liver biopsies from these patients show predominant iron accumulation in reticuloendothelial cells, sometimes with coexistent hepatocyte iron loading. The second non-classical subtype of ferroportin disease has a phenotypic presentation more similar to other adult onset forms of autosomal recessive HH caused by mutations in HFE or TFR2. It is characterized by elevated transferrin saturation and serum ferritin, with iron accumulation in hepatocytes. These two subtypes of ferroportin disease can be explained by mutations that affect different facets of ferroportin function.