Published online 27 January 2009
Haematologica, Vol 94, Issue 3, 335-339 doi:10.3324/haematol.2008.000125
Copyright © 2009 by Ferrata Storti Foundation

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Original Article

A new missense mutation in the L ferritin coding sequence associated with elevated levels of glycosylated ferritin in serum and absence of iron overload

Caroline Kannengiesser^1,3, Anne-Marie Jouanolle², Gilles Hetet¹, Annick Mosser², Françoise Muzeau³, Dominique Henry¹, Edouard Bardou-Jacquet², Martine Mornet⁴, Pierre Brissot⁵, Yves Deugnier⁵, Bernard Grandchamp^1,3, Carole Beaumont³

¹ AP-HP, Service de Génétique et Biochimie hormonale, Hôpital Bichat Claude Bernard, Paris, France, Université Paris Diderot, Paris;
² Laboratoire de Génétique Moléculaire, Hôpital Pontchaillou, Rennes;
³ INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon, Université Paris Diderot, Paris;
⁴ Service de Médecine Interne, Centre Hospitalier Jacques Cœur, Bourges and
⁵ Service des Maladies du Foie et Centre de Référence des Surcharges Génétiques en Fer, Hôpital Pontchaillou, Rennes, France

Correspondence: Carole Beaumont, INSERM U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, Université Paris Diderot, site Bichat BP416, 16 Rue Henri Huchard, 75870 Paris cedex 18, France., E-mail:carole.beaumont{at}inserm.fr

Background: Elevated serum ferritin levels are frequently encountered in clinical situations and once iron overload or inflammation has been ruled out, many cases remain unexplained. Genetic causes of hyperferritinemia associated to early cataract include mutations in the iron responsive element in the 5’ untranslated region of the L ferritin mRNA, responsible for the hereditary hyperferritinemia cataract syndrome.

Design and Methods: We studied 91 probands with hyperferritinemia comprising 25 family cases belonging to families with at least two cases of unexplained hyperferritinemia, and 66 isolated cases. In the families, we also analyzed 30 relatives. Hyperferritinemia was considered as unexplained when transferrin saturation was below 45% and/or serum iron below 25 µmol/L and/or no tissue iron excess was detected, when inflammation had been ruled out and when iron responsive element mutation was absent. We carried out sequencing analysis of the FTL gene coding the L ferritin.

Results: A novel heterozygous p.Thr30Ile mutation in the NH2 terminus of L ferritin subunit was identified in 17 probands out of the cohort. The mutation was shown to cosegregate with hyperferritinemia in all the 10 families studied. No obvious clinical symptom was found associated with the presence of the mutation. This unique mutation is associated with an unusually high percentage of ferritin glycosylation.

Conclusions: This missense mutation of FTL represents a new cause of genetic hyperferritinemia without iron overload. We hypothesized that the mutation increases the efficacy of L ferritin secretion by increasing the hydrophobicity of the N terminal "A" helix.

Key words: hyperferritinemia, glycosylated ferritin, L ferritin, iron overload.

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