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Case report: a subject with a mutation in the ATG start codon of L-ferritin has no haematological or neurological symptoms
  1. L Cremonesi1,
  2. A Cozzi2,
  3. D Girelli3,
  4. F Ferrari1,
  5. I Fermo4,
  6. B Foglieni1,
  7. S Levi2,
  8. C Bozzini3,
  9. M Camparini5,
  10. M Ferrari1,
  11. P Arosio6
  1. 1Genomics for the Diagnosis of Human Pathologies Unit, IRCCS H. San Raffaele, Via Olgettina 58, 20132 Milan, Italy
  2. 2Protein Engineering Unit, IRCCS H. San Raffaele, Via Olgettina 58, 20132 Milan, Italy
  3. 3Department of Clinical and Experimental Medicine, University of Verona, Policlinico G.B. Rossi, 37134 Verona, Italy
  4. 4Separative Techniques Unit, IRCCS H. San Raffaele, Via Olgettina 60, 20132 Milan, Italy
  5. 5Section of Ophthalmology, University of Parma, 43100 Parma, Italy
  6. 6Section of Chemistry, Faculty of Medicine, University of Brescia, 25100 Brescia, Italy
  1. Correspondence to:
 Professor Paolo Arosio
 Department MITB, Viale Europa 11, 25125 Brescia, Italy;

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Ferritin consists of two subunit types, H and L, which assemble in different proportions in a 24-mer protein.1 The H-subunit has ferroxidase activity and is mainly found in cell cytoplasm, where it has the major function of sequestering and detoxifying unwanted iron. The L-subunit has no catalytic activity on its own, but assists the functionality of the H-subunit2 and is also found in minor amounts in serum.3 Two types of genetic disorder are associated with mutations of the L-ferritin gene (FTL), both with autosomal dominant transmission. The first, hereditary hyperferritinaemia cataract syndrome (HHCS), is caused by mutations in the regulatory iron responsive element (IRE) in the 5′UTR of the transcript that reduce binding affinity to the iron regulatory proteins (IRPs) and lead to constitutive upregulation of the protein in tissue and serum.4–8 Subjects with the mutations show high levels of serum ferritin (500–2000 μg/l) and often early-onset bilateral cataracts6 likely caused by protein aggregation in the lens,9 but do not present alterations in iron metabolism. The disorder has been extensively studied and more than 21 different causative mutations have been identified.9,10 The second type of genetic disorder, neuroferritinopathy, is rare and few families have been identified. It is associated with an adenine insertion at position 460–461 in the coding region (exon 4) of the gene that causes a frame shift alteration of the C-terminus of the L-ferritin polypeptide.11 Affected subjects show late-onset movement disorders, iron deposition in the brain basal ganglia, and low serum ferritin levels.12,13 It is unclear whether the iron deposition in the brain is caused by a quantitative defect of L-ferritin or by an abnormal functionality caused by …

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  • This work was partially supported by MIUR-Cofin grants to PA, a MIUR-Cofin grant to PA and SL, and by Telethon-Italy Grant GP0075Y01 to SL.

  • Conflict of interest: none declared.