Albertine Donker

General Introduction 31 1 Figure 5. TMPRSS6 defects cause inappropriately increased hepcidin levels, resulting in Iron Refractory Iron Deficiency Anemia Matriptase-2 HJV BMPR BMP HAMP Hepcidin Normal Hepcidin Matriptase-2 deficiency absorption release recycling Fe2 + IRIDA  Matriptase-2 HJV BMPR BMP HAMP  (+) A B Matriptase 2, encoded by TMPRSS6, plays an essential role in providing adequate iron supply to the erythroblasts and other iron-demanding tissues by down-regulating hepcidin (see also Figure 2). A . Physiological situation. MT2 prevents hepcidin overexpression by degrading HJV, which acts as a co-factor for BMP to promote HAMP expression, resulting in hepcidin synthesis. B . Pathogenic TMPRSS6 defects leading to matriptase 2 deficiency result in uninhibited hepcidin production despite low body iron levels, due to aberrant cleavage of HJV. This causes IRIDA, a disease characterized by a microcytic, hypochromic anemia due to serum hepcidin values that are inappropriately high for circulating iron levels. Abbreviations: BMP denotes bone morphogenetic protein; BMPR, BMP receptor; Fe 2+ , ferrous iron; HJV, hemojuvelin; IRIDA, Iron Refractory Iron Deficiency Anemia. Figure adapted from Cui et al , 2009. 109 IRIDA patients typically present in childhood with microcytic anemia not responding to oral iron, in combination with remarkably low TSAT, which tends to become less severe with increasing age. 110 At the population level, genome wide association studies (GWAS) show that TMPRSS6 is polymorphic with a relatively high frequency of polymorphisms of which the non-synonymous c.2207C>T (p.Ala736Val) is associated with a significant decrease of the concentrations of iron, Hb, Ht, MCV, MCH and red blood cells. 111,112 These findings are corroborated by functional studies, which show that the 736Ala variant inhibits hepcidin production more efficiently, although GWAS do not support an intermediate role for hepcidin in iron parameters associations. This suggests that other, yet unknown serum hepcidin-independent mechanisms play a role in the association of the p.Ala736Val TMPRSS6 variant with serum iron parameters. 113-115