PMC4296220_01
(A) Pedigree showing autosomal dominant inheritance of hyperferritinemia with cataracts. Solid symbol, affected; open symbol, unaffected, gray symbol, unknown; arrow, proband (P). (B) Sequence chromatogram of the FTL gene from the proband (upper panel) and his mother (lower panel), showing the heterozygous c.-160A>G mutation (arrow; Reference Sequence NM_000146.3). (C) IRE prediction of wild-type FTL mRNA showing the mutation site (arrow) in the apical loop which binds IRPs. Bioinformatic analysis of c.-160A>G mutant FTL did not predict an IRE. (D) Schematic diagram showing how the c.-160A>G mutation causes loss of normal IRE-IRP-mediated repression of FTL expression at low intracellular iron concentrations, causing unregulated L-ferritin synthesis, in the absence of iron overload, in HHCS.
hep0059-1204-f1.jpg
PMC4296220_01_hep0059-1204-f1.jpg
fig01
He did, however, have a family history of hemochromatosis in a pattern suggestive of autosomal dominant inheritance (Fig. 1A) and a personal history of bilateral rheumatoid factor negative arthritis affecting his ankles and knees which had resolved spontaneously after 6 months and of bilateral cataract removal the previous year. A heterozygous c.-160A>G mutation was identified in the IRE within the 5' untranslated region (5'-UTR) of FTL, in the patient and his mother (Fig 1B). Bioinformatic analysis (http://ccbg.imppc.org/sires/index.html) predicted that the mutant messenger RNA (mRNA) will not form the regulatory IRE "hairpin" structure (Fig 1C). Subsequent investigation showed that the inheritance of hyperferritinemia in this family coincided with the inheritance of bilateral cataracts (Fig. 1A). IREs and so decrease translation of ferritin subunits. In HHCS, the IRE mutation reduces IRP binding and impairs the normal suppression of FTL translation at low intracellular iron concentrations, so serum ferritin concentrations are elevated in the absence of iron loading (Fig 1D).