PIGA mutations (can) cause juvenile hemochromatosis. Hemochromatosis is the most frequent iron overload disorder in humans. (A) The clinical symptoms that can be provoked by iron overload. Affected organs are typically the pituitary gland, the heart, the liver, pancreas, testes, and the joints. Newly reported in the current paper are neurologic symptoms. (B) Normal iron absorption is depicted in the upper panel. Signaling downstream of HFE, HJV, and TFR2 induce the expression of the iron regulatory hormone hepcidin (green dots). Hepcidin is synthesized by hepatocytes and binds to and inactivates the iron exporter ferroportin (blue channel). Iron (Fe²⁺, red dots) is incorporated into the enterocyte via DMT1 (green channel) and exported via ferroportin into the blood. Soluble ceruloplasmin oxidizes Fe²⁺ to Fe³⁺, which, in turn, is bound to transferrin and transported to the bone marrow for erythropoiesis. Typically, hemochromatosis develops owing to mutations in the hemochromatosis gene, HFE (B lower panel), HJV, TFR2, hepcidin, or ferroportin.² Either reduced hepcidin synthesis is caused by one of these mutations or a mutation in ferroportin leads to excessive iron accumulation. Mutations in HJV or hepcidin cause the most severe form of iron overload, juvenile hemochromatosis. HJV and membrane-bound ceruloplasmin are GPI-linked proteins, as shown in the lower panel. The authors of the current paper identified mutations in phosphatidylinositol glycan anchor biosynthesis class A (PIGA), an enzyme involved in GPI-anchor biosynthesis in 3 patients with clinical symptoms of hemochromatosis and neurologic symptoms. TRF1, transferrin receptor 1. Professional illustration by Patrick Lane, ScEYEnce Studios.