A Point Mutation in the Bulge of the Iron-Responsive Element of the L Ferritin Gene in Two Families With the Hereditary Hyperferritinemia-Cataract Syndrome

Abstract

The molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome is the presence of a mutation in the iron-responsive element (IRE) of the L ferritin gene, located on chromosome 19q13.3-13.4. Two mutations have been reported so far, altering adjacent nucleotides in the IRE loop, in a region that has been extensively studied in vitro and shown to mediate high affinity interaction with the iron-responsive protein. In this report, we describe two families with a new mutation in the bulge of the IRE stem, and we show that this mutation alters the protein-binding affinity of the IRE in vitro to the same extent as the loop mutation. In addition, we present evidence that some variability in the age of onset of cataract can be associated with this genetic syndrome, probably because of additional genetic or environmental factors that modulate the penetrance of the L ferritin defect in the lens. We confirm that the patients do not have increased iron stores despite the persistence of elevated serum ferritin levels and that, accordingly, they do not tolerate well venesection therapy. Further studies will be necessary to elucidate the mechanism responsible for the onset of cataract.

Hereditary Hyperferritinemia-Cataract Syndrome

“…6 A series of 11 different point mutations and 4 small deletions in the IRE of the ferritin light chain mes-senger RNA have subsequently been shown to cause HHCS by preventing binding of the inhibitory iron regulatory protein to the IRE stem loop structure, leading to constitutively expressed high-level ferritin light chain translation independent of iron stores. [7][8][9][10][11][12][13][14][15][16] Thus, affected individuals typically exhibit dramatically elevated serum ferritin levels in the absence of iron overload.…”

A new mutation (G51C) in the iron‐responsive element (IRE) of l‐ferritin associated with hyperferritinaemia–cataract syndrome decreases the binding affinity of the mutated IRE for iron‐regulatory proteins

“…Hereditary hyperferritinaemia±cataract syndrome (HHCS) is an autosomal dominant disorder associated with mutations in the iron-responsive element (IRE) of L-ferritin mRNA, which reduce the af®nity for the iron-regulatory proteins (IRPs) (Beaumont et al, 1995;Girelli et al, 1995Girelli et al, , 1997Aguilar-Martinez et al, 1996;Cazzola et al, 1997;Martin et al, 1998;Mumford et al, 1998;Balas et al, 1999). This results in a decrease of iron-mediated down-regulation of Lferritin translation (Levi et al, 1998).…”

“…As a consequence, the patients who carry these mutations show abnormally high levels of serum ferritin unrelated to body iron stores and often also the early onset of bilateral cataract, apparently related to an excess ferritin accumulation in the lens (Cicilano et al, 1999). Nine different mutations in HHCS have been described so far (Beaumont et al, 1995;Girelli et al, 1995Girelli et al, , 1997Aguilar-Martinez et al, 1996;Cazzola et al, 1997;Martin et al, 1998;Mumford et al, 1998;Balas et al, 1999) with some occurring in unrelated families (Cicilano et al, 1999), which indicates their causal role in the disorder. Although some variation of the phenotypic expression has been observed among subjects of the same families (Cicilano et al, 1999), it has been noted that mutations affecting the upper loop or the lateral bulge determine higher levels of serum ferritin and more evident cataract than the mutations in the lower part of the IRE structure (Cazzola et al, 1997).…”

A Point Mutation in the Iron-Responsive Element of the L-Ferritin in a Family with Hereditary Hyperferritinemia Cataract Syndrome

“…DNA analysis identified a heterozygous mutation (G32T) in the bulge of the IRE in the affected members. This mutation has also been described in six individuals in France (11,12) and one family in Australia (4). The G32T mutation has previously been shown to lead to a decrease in binding affinity of IRE to the IRP by in vitro gel retardation assays performed by Martin et al (12).…”