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.
Hetet
Gilles
G
INSERM U409, Faculte Xavier Bichat, 16 rue Henri Huchard, BP 416, 75870 Paris cedex 18, France.
Devaux
Isabelle
I
Soufir
Nadem
N
Grandchamp
Bernard
B
Beaumont
Carole
C
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