Patients with deficiency in
ferrochelatase (FECH), the last
enzyme of the
heme biosynthetic pathway, experience a painful type of skin photosensitivity called
erythropoietic protoporphyria (EPP), which is caused by the excessive production of
protoporphyrin IX (
PPIX) by erythrocytes. Controversial results have been reported regarding hematologic status and
iron status of patients with EPP. We thoroughly explored these parameters in Fechm1Pas mutant mice of 3 different genetic backgrounds. FECH deficiency induced microcytic
hypochromic anemia without ringed sideroblasts, little or no
hemolysis, and no erythroid
hyperplasia. Serum
iron,
ferritin,
hepcidin mRNA, and Dcytb levels were normal. The homozygous Fechm1Pas mutant involved no tissue
iron deficiency but showed a clear-cut redistribution of
iron stores from peripheral tissues to the spleen, with a concomitant 2- to 3-fold increase in
transferrin expression at the
mRNA and the
protein levels. Erythrocyte
PPIX levels strongly correlated with serum
transferrin levels. At all stages of differentiation in our study,
transferrin receptor expression in bone marrow erythroid cells in Fech(m1Pas) was normal in mutant mice but not in patients with
iron-deficiency anemia. Based on these observations, we suggest that oral
iron therapy is not the
therapy of choice for patients with EPP and that the
PPIX-liver
transferrin pathway plays a role in the orchestration of
iron distribution between peripheral
iron stores, the spleen, and the bone marrow.