Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)

Abstract

Iron deficiency is usually attributed to chronic blood loss or inadequate dietary intake. Here, we show that iron deficiency anemia refractory to oral iron therapy can be caused by germline mutations in TMPRSS6, which encodes a type II transmembrane serine protease produced by the liver that regulates the expression of the systemic iron regulatory hormone hepcidin. These findings demonstrate that TMPRSS6 is essential for normal systemic iron homeostasis in humans.

Figure 1

Schematic representation of TMPRSS6 mutations and corresponding TMPRSS6 domains. The missense, nonsense, frameshift and splice junction mutations present in five familial and two sporadic cases of IRIDA are diagrammed adjacent to the affected TMPRSS6 domain (Table 1). The transmembrane (TM), complement factor C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein (CUB), LDL-receptor class A (L) and trypsin-like serine protease domains are shown in green, blue, yellow and red, respectively.