Ferritin H- and L-chains form a shell of 24 subunits that stores iron. Each type of chain has a distinct role in iron storage. The H-chain is encoded by the FTH1 gene (chromosome 11q12–q13) and the L-chain by the FTL gene (chromosome 19q13.13–13.4). A common cytosolic protein, iron regulatory protein (IRP), binds to the iron-responsive element (IRE) of the 5′ untranslated regions (UTRs) of the H- and L-subunit RNAs, and thus controls the synthesis of both proteins. Heterogeneous mutations in the IRE of L-ferritin reduce the binding affinity of IRE to IRPs and thereby diminish the negative control of L-ferritin (but not H-ferritin) synthesis. This leads to the constitutive upregulation of ferritin L-chain synthesis characteristic of the autosomal dominant disorder known as hereditary hyperferritinemia-cataract syndrome (HHCS) (Chapter 17). In 2001, Kato and colleagues described a unique Japanese family in which a mutation in the H-ferritin IRE (A49U) caused hyperferritinemia and autosomal dominant iron overload (OMIM +134770).

Clinical description

The proband, a 56-year-old woman, was discovered to have a markedly increased liver density on computerized tomography scanning. A T2-weighted magnetic resonance imaging study also showed markedly decreased signal intensity in the liver; signal intensity in the heart and bone marrow was similar to that of the liver. These results were interpreted as iron overload; this was confirmed by her serum ferritin level of 1654 μg/L. She had elevated serum iron and transferrin saturation measures and normal total iron-binding capacity.