Iron is a vitally important
element in mammalian metabolism because of its unsurpassed versatility as a
biologic catalyst. However, when not appropriately shielded or when present in excess,
iron plays a key role in the formation of extremely toxic
oxygen radicals, which ultimately cause peroxidative damage to vital cell structures. Organisms are equipped with specific
proteins designed for
iron acquisition, export, transport, and storage as well as with sophisticated mechanisms that maintain the intracellular labile
iron pool at an appropriate level. These systems normally tightly control
iron homeostasis but their failure can lead to
iron deficiency or
iron overload and their clinical consequences. This review describes several rare
iron loading conditions caused by genetic defects in some of the
proteins involved in
iron metabolism. A dramatic decrease in the synthesis of the plasma
iron transport protein,
transferrin, leads to a massive accumulation of
iron in nonhematopoietic tissues but virtually no
iron is available for erythropoiesis. Humans and mice with hypotransferrinemia have a remarkably similar phenotype. Homozygous defects in a recently identified gene encoding
transferrin receptor 2 lead to
iron overload (
hemochromatosis type 3) with symptoms similar to those seen in patients with HFE-associated hereditary
hemochromatosis (
hemochromatosis type 1).
Transferrin receptor 2 is primarily expressed in the liver but it is unclear how mutant forms cause
iron overload. Mutations in the gene encoding the
iron exporter,
ferroportin 1, cause
iron overload characterized by
iron accumulation in macrophages yet normal plasma
iron levels. Plasma
iron, together with dominant inheritance, discriminates
iron overload due to
ferroportin mutations (
hemochromatosis type 4) from
hemochromatosis type 1.
Heme oxygenase 1 is essential for the catabolism of
heme and in the recycling of
hemoglobin iron in macrophages. Homozygous
heme oxygenase 1 deletion in mice leads to a paradoxical accumulation of nonheme
iron in macrophages, hepatocytes, and many other cells and is associated with low plasma
iron levels,
anemia, endothelial cell damage, and decreased resistance to oxidative stress. A similar phenotype occurred in a child with severe
heme oxygenase 1 deficiency. Recently, a mutation in the L-subunit of
ferritin has been described that causes the formation of aberrant
L-ferritin with an altered C-terminus. Individuals with this mutation in one allele of
L-ferritin have abnormal aggregates of
ferritin and
iron in the brain, primarily in the globus pallidus. Patients with this dominantly inherited
late-onset disease present with symptoms of extrapyramidal dysfunction. Mice with a targeted disruption of a gene for
iron regulatory protein 2 (IRP2), a translational repressor of
ferritin, misregulate
iron metabolism in the intestinal mucosa and the central nervous system. Significant amounts of
ferritin and
iron accumulate in white matter tracts and nuclei, and adult IRP2-deficient mice develop a
movement disorder consisting of
ataxia,
bradykinesia, and
tremor. Mutations in the
frataxin gene are responsible for
Friedreich ataxia, the most common of the inherited
ataxias.
Frataxin appears to regulate mitochondrial
iron (or
iron-
sulfur cluster) export and the neurologic and cardiac manifestations of
Friedreich ataxia are due to
iron-mediated mitochondrial toxicity. Finally, patients with
Hallervorden-Spatz syndrome, an autosomal recessive, progressive
neurodegenerative disorder, have mutations in a novel
pantothenate kinase gene (PANK2). The cardinal feature of this extrapyramidal disease is pathologic
iron accumulation in the globus pallidus. The defect in PANK2 is predicted to cause the accumulation of
cysteine, which binds
iron and causes oxidative stress in the
iron-rich globus pallidus.