Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and 3 new ferroportin (slc11A3) mutations.
Unexplained hyperferritinemia is a common clinical finding, even in asymptomatic persons. When early onset bilateral cataracts are also present, the hereditary hyperferritinemia-cataract syndrome (HHCS), because of heterozygous point mutation in the L ferritin iron-responsive element (IRE) sequence, can be suspected. We sequenced the L ferritin exon 1 in 52 DNA samples from patients referred to us for molecular diagnosis of HHCS. We identified 24 samples with a point mutation/deletion in the IRE. For the 28 samples in which no IRE mutation was present, we also genotyped HFE mutations and sequenced both H ferritin and ferroportin genes. We found an increased frequency of His63Asp heterozygotes (12 of 28) but no H ferritin mutations. We identified 3 new ferroportin mutations, producing, respectively, Asp157Gly, Gln182His, and Gly323Val amino acid replacements, suggesting that these patients have dominant type 4 hemochromatosis. This study demonstrates that both L ferritin IRE and ferroportin mutations can account for isolated hyperferritinemia. The presence of cataract does not permit the unambiguous identification of patients with HHCS, although the existence of a family history of cataract was only encountered in these patients. This raises the intriguing possibility that lens ferritin accumulation might be a factor contributing to age-related cataract in the general population. Additional causes of isolated hyperferritinemia remain to be identified.
INSERM U409, Faculte Xavier Bichat, 16 rue Henri Huchard, BP 416, 75870 Paris cedex 18, France.
Gilles
G
Hetet
Isabelle
I
Devaux
Nadem
N
Soufir
Bernard
B
Grandchamp
Carole
C
Beaumont
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001052:Apoferritins; D002386:Cataract / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D005293:Ferritins / Q000097:blood*; D017353:Gene Deletion; D006801:Humans; D007501:Iron / Q000097:blood; D019189:Iron Metabolism Disorders / Q000097:blood* / Q000235:genetics*; D035941:Iron Regulatory Protein 1 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D017354:Point Mutation; D000098742:Ferroportin
D027682:Cation Transport Proteins; D000098742:Ferroportin; D005293:Ferritins; D001052:Apoferritins; D007501:Iron; D035941:Iron Regulatory Protein 1