Hereditary hyperferritinemia-cataract syndrome: a novel mutation in the iron-responsive element of the L-ferritin gene in a French family

Abstract

Hereditary hyperferritinemia-cataract syndrome is an autosomal dominant disease characterized by constitutively increased L-ferritin production in the absence of iron overload and by bilateral cataracts. It is related to an abnormality in the mechanism controlling ferritin availability (1Beaumont C Leneuve P Devaux I et al.Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinemia and cataract.Nat Genet. 1995; 11: 444-446Crossref PubMed Scopus (264) Google Scholar). Mutations in the iron-responsive element of the L-ferritin gene are thought to disrupt iron-responsive element interaction with a cytoplasmic iron regulatory protein, leading to constitutive L-ferritin production. In 1997, Cazzola et al reported a single- and double-point mutation in two families with hyperferritinemia-cataract syndrome (2Cazzzola M Bergamaschi G Tonon L et al.Hereditary hyperferritinemia-cataract syndrome: relationship between phenotypes and specific mutations in the iron-responsive element of ferritin light-chain mRNA.Blood. 1997; 90: 814-821PubMed Google Scholar). Other mutations have been detected since. We report a novel iron-responsive element mutation in a French family with hyperferritinemia-cataract syndrome. An apparently healthy 27-year-old woman showed persistently high ferritin levels (1220 ng/mL) in routine blood tests. The patient had no personal history of disease and no liver or inflammatory disease suggesting hyperferritinemia. Serum iron and transferrin saturation levels were normal and a liver magnetic resonance imaging scan confirmed the absence of iron overload 55 μmol/g. Examination of the eyes revealed an early bilateral cataract in the lens periphery. The patient had a family history of bilateral cataract (the patient's mother, who underwent surgery at the age of 25, and maternal grandfather). Our observations led us to suspect hyperferritinemia-cataract syndrome. Iron parameters were assessed in members of the family. Ferritin level in the mother was 1107 ng/mL and in the grandfather was 2027 ng/mL. Neither had an iron overload. Transferrin saturation levels were 40% in the mother and 41% in the grandfather. Genomic DNA was extracted from peripheral blood with QIAamp DNA Blood Mini Kit (Qiagen, Courtabeuf, France). The entire iron-responsive element sequence of the L-ferritin subunit gene was amplified by polymerase chain reaction using appropriate primers (3Girelli D, Corrocher R, Bisceglia, et al. Molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome: a mutation in the iron-responsive element of ferritin L-subunit gene (the <<Verona mutation>>). Blood.1995; 86:4050–4053Google Scholar), and both sense and antisense were directly sequenced. A heterozygous +39 C→G substitution was detected in the apical loop of the iron-responsiveness element from the proband from her mother and grandfather but not in the iron-responsive element from other family members (Figure). Our finding is consistent with in vitro and in vivo observations suggesting that mutations near the iron-responsive element apex result in exceptionally high serum ferritin levels and dense cataracts (4Bettany A.J.E Eisenstein R.S Munro H.N Mutagenesis of iron-regulatory element further defines a role for RNA secondary structure in the regulation of ferritin and transferrin receptor expression.J Biol Chem. 1992; 267: 16531-16537Abstract Full Text PDF PubMed Google Scholar, 5Jaffrey S.R Haile D.J Klausner R.D Harford J.B The interaction between the iron-responsive element and its cognate RNA is highly dependent upon both RNA sequence and structure.Nucleic Acids Res. 1993; 21: 4627-4631Crossref PubMed Scopus (89) Google Scholar, 6Cicilano R Zecchina G Roetto A et al.Recurrent mutations in the iron regulatory element of L-ferritin in hereditary hyperferritinemia-cataract syndrome.Haematologica. 1999; 84: 489-492PubMed Google Scholar). In this regard, a heterozygous +39 C→U substitution has been reported with a similar phenotype (7Hetet G Devaux I Soufir N et al.Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and 3 new ferroportin (slc 11A3) mutations.Blood. 2003; 102: 1904-1910Crossref PubMed Scopus (118) Google Scholar). The ferroportin gene was also sequenced, as mutations of this gene have been detected in patients with unexplained hyperferritinemia and low transferring saturation (7Hetet G Devaux I Soufir N et al.Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and 3 new ferroportin (slc 11A3) mutations.Blood. 2003; 102: 1904-1910Crossref PubMed Scopus (118) Google Scholar). No mutation of the ferroportin gene was found. Clinicians faced with a high serum ferritin level without iron overload in an apparently healthy person should be encouraged to search for this new iron-responsive element mutation after excluding inflammation and liver disease. If the mutation is present, no treatment is needed and, in particular, no phlebotomy should be performed. There is currently no treatment to prevent lens opacity.