Increased plasma transferrin, altered body iron distribution, and microcytic hypochromic anemia in ferrochelatase-deficient mice

Abstract

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 Fech m1Pas 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 Fech m1Pas 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 PPIXliver transferrin pathway plays a role in the orchestration of iron distribution between peripheral iron stores, the spleen, and the bone marrow. IntroductionErythropoietic protoporphyria (EPP; Mendelian Inheritance in Man [MIM] 177000) is an inherited disorder caused by partial deficiency of ferrochelatase (FECH; EC 4.99.1.1.), the last enzyme of the heme biosynthetic pathway. 1 FECH is an inner membrane mitochondrial enzyme catalyzing the insertion of ferrous iron into protoporphyrin IX (PPIX) to form heme. FECH deficiency in bone marrow erythroid cells is responsible for the primary overproduction of PPIX, leading to an accumulation of protoporphyrin in the bone marrow, plasma, erythrocytes, skin, bile, and feces. 2 Because of its hydrophobic nature, PPIX can be removed from the body only through the liver, where it is secreted into bile and then is excreted by fecal elimination. 3 More than100 mutations in the FECH gene, including missense, nonsense, splicing, deletions, and insertions, have been identified in EPP families (Human Gene Mutation Database, http:// archive.uwcm.ac.uk/uwcm/mg/hgmd0.html). Usually, EPP is inherited as an autosomal pseudodominant disorder, and clinical penetrance is mainly modulated by the presence of a common intronic single-nucleotide polymorphism (SNP), IVS3-48C, in trans to a dominant mutation. 4,5 The most common clinical manifestation of EPP is lifelong acute photosensitivity of sun-exposed skin appearing in early childhood. 6 Although EPP is generally a benign disease, hepatic complications such as cholelithiasis or, in rare cases (approximately 2%), rapid fatal liver disease with cirrhosis may occur. [7][8][9] Chronic liver disease i...

Red cells from ferrochelatase-deficient erythropoietic protoporphyria patients are resistant to growth of malarial parasites

“…Mice homozygous for the allele have 5% and heterozygotes 45% to 65% residual enzyme activity compared with wild-type mice. 32 Homozygous Fech m1Pas mice (isogenic with C57BL/6) infected with P chabaudi were significantly more resistant to the infection than their heterozygous and wild-type littermates. There was an almost twofold reduction in peak parasitemia levels (Figure 2A,C) and 2 to 3 times greater rates of survival ( Figure 2B,D).…”

Hemolytic anemia repressed hepcidin level without hepatocyte iron overload: lesson from Günther disease model

“…20 The results were arbitrarily normalized using the sample with the lowest C T value for S14, actin or GAPDH, as indicated. The relative quantifications were calculated using the comparative CT method.…”

Protective effects of lycopene on oxidative stress, proliferation and autophagy in iron supplementation rats

“…The tissue iron contents were determined by acid digestion of tissue samples as described previously (Lyoumi et al, 2007;, followed by iron quantification using a commercial kit, according to manufacture's instructions.…”