Albertine Donker

Chapter 10 336 (IRIDA) and x-linked sideroblastic anemia (XLSA). We aimed to increase awareness for these rare disorders, to facilitate the diagnostic process, enabling the timely start of an adequate treatment, with the ultimate goal of reducing the disease burden and preventing lifelong sequelae of either iron deficiency or iron overload for the individual patient. Chapter 1 is the general introduction to this thesis, describing the (patho)physiology of systemic and cellular iron metabolism and heme synthesis. Iron can participate in electron transfer by the interconversion between Fe 2+ and Fe 3 and this fundamental biochemical characteric makes virtually all tissues in the human body dependent of iron. However, the majority of iron is dedicated to the synthesis of the iron-containing hemoglobin inside the erythrocytes, crucial for oxygen transport. Therefore, deficit of iron results in the clinical condition of iron deficiency anemia, affecting over 1.2 billion people globally. On the other hand, iron is also potentially toxic to cells because unbound iron can catalyze the formation of oxidative radicals that damage proteins, lipids and nucleic acids. Furthermore, many pathogens are dependent of iron for their survival. Because both iron deficiency and iron overload may have detrimental effects, a highly sophisticated regulatory system is required to maintain iron homeostasis on both the systemic and cellular level. In this introductory chapter, the two regulatory systems responsible for body iron homeostasis are described, one that functions systemically and is dependent on the liver-derived hormone hepcidin, and the other that predominantly controls cellular iron metabolism through iron-regulatory proteins (IRP) that bind iron-responsive elements (IRE) in regulated messenger RNA’s of cellular iron importers, exporters and storage genes. Although the machineries of systemic and cellular iron homeostasis are separated, crosstalk exists between the two distinct control systems, which is explained. Since this thesis also addresses genetic disorders of heme synthesis, especially XLSA due to ALAS2 defects, we explain the eight steps of heme biosynthesis, for which ALAS2 is crucial for the first and rate-limiting step.