An inherited disease affecting the iron-binding protein ferritin

Some genetic disorders are comparatively common, such as sickle-cell anaemia, discussed in the previous chapter. However, there are also disorders that are extremely rare. Here we will deal with one such example, hyperferritinaemia cataract syndrome (Beaumont et al., 1995; Girelli et al., 1995, 1996, 1997; Kato et al., 2001). It results in high levels of the protein ferritin in the blood. Another symptom is cataracts, i.e. clouding of the lens of the eye. The first cases of this disorder were described in 1995 (Beaumont et al., 1995; Girelli et al., 1995). One of the reports was concerned with two families that had lived in northern Italy for many generations (Girelli et al., 1995). The affected family members already had symptoms of glare and impaired visual acuity in childhood. They also had high serum levels of ferritin. It was soon found that the molecular basis of the disease is a mutation in the ferritin mRNA. In the previous chapter we encountered inherited diseases that are the result of a mutation in the coding sequence of the gene, as exemplified by sickle-cell anaemia, Lesch–Nyhan syndrome and Huntington's disease. However, in the case of hyperferritinaemia cataract syndrome the mutation is not in the coding sequence. Instead, it affects a regulatory region in the 5′ untranslated region (UTR) of the ferritin mRNA (for a description of UTR, see Fig. 1.1).

Many proteins of iron metabolism are regulated at the level of translation

What is the function of ferritin? Free iron ions are toxic to cells and an important protective function of ferritin is to bind these ions. The production of the ferritin protein is carefully regulated in order to maintain a suitable level of free ions and to optimize the interaction with other proteins involved in iron metabolism. (For more on the intricate and complex pathways of iron metabolism, see Outten and Theil, 2009; Hentze et al., 2010.) The regulation of ferritin production is exerted through an intriguing mechanism involving translation of its mRNA (Fig. 6.1). In the ferritin mRNA a local RNA hairpin structure, the iron responsive element (IRE), is located in the 5′ UTR (Fig. 6.2). In cells that are starved of iron, the IREs are targets of two cytoplasmic regulatory proteins, IRP1 and IRP2 (Volz, 2008). The binding of these proteins to IRE results in repression of translation, and hence lowered expression of ferritin. When iron is abundant, the IRP proteins tend to have lower affinity to IREs, and as a result ferritin translation is efficient.