HEREDITARY HYPERFERRITINEMIA-CATARACT SYNDROME - RELATIONSHIP BETWEENPHENOTYPES AND SPECIFIC MUTATIONS IN THE IRON-RESPONSIVE ELEMENT OF FERRITIN LIGHT-CHAIN MESSENGER-RNA

Recent reports have described families in whom a combination of elevat ed serum ferritin not related to iron overload and congenital nuclear cataract is transmitted as an autosomal dominant trait. We have studie d the molecular pathogenesis of hyperferritinemia in two families show ing different phenotypic expression of this new genetic disorder, Seru m ferritin levels ranged from 950 to 1,890 mu g/L in affected individu als from family 1, and from 366 to 635 mu g/L in those from family 2, Cataract was clinically manifested in family 1 and asymptomatic in fam ily 2. By using monoclonal antibodies specific for the H and L ferriti n subunits, serum ferritin was found to be essentially L type in both normal and affected individuals. The latter also showed normal amounts of H-type ferritin in circulating mononuclear cells; on the contrary, L-type ferritin contents were 13 times normal in family 1 and five ti mes normal in family 2 on average. Serum ferritin was glycosylated in both normal and affected individuals. There was a close relationship b etween mononuclear cell L-type ferritin content and serum ferritin con centration (r = 0.95, P < .00001), suggesting that the excess producti on of ferritin in cells was directly responsible for the hyperferritin emia. The dysregulated L-subunit synthesis was found to result from di fferent point mutations in a non-coding sequence of genomic L-subunit DNA, which behaves as an mRNA cis-acting element known as iron regulat ory element (IRE), Affected individuals from family 1 were heterozygou s for a point mutation (a single G to A change) in the highly conserve d, three-nucleotide motif forming the IRE bulge. Affected members from family 2 were heterozygous for a double point mutation in the IRE low er stem, Using a gel retardation assay, the observed molecular lesions were shown to variably reduce the IRE affinity for an iron regulatory protein (IRP), which inhibits ferritin mRNA translation. The direct r elationship between the degree of hyperferritinemia and severity of ca taract suggests that this latter is the consequence of excessive ferri tin production within the lens fibers, These findings provide strong e vidence that serum ferritin is a byproduct of intracellular ferritin s ynthesis and that the L-subunit gene on chromosome 19 is the source of glycosylated serum ferritin, From a practical standpoint, this new ge netic disorder should be taken into account by clinicians when facing a high serum ferritin in an apparently healthy person. (C) 1997 by The American Society of Hematology.