title: Hereditary hyperferritinemia cataract syndrome in three unrelated families of western Greek origin caused by the C39 > G mutation of L-ferritin IRE.
abstract: Hereditary hyperferritinemia-cataract syndrome (HHCS) is a well-characterized autosomal dominant disease caused by mutations in the iron responsive element (IRE) of ferritin L-chain (FTL) mRNA. Mutations in the IRE result in reduced binding of the trans-acting iron regulatory proteins (IRPs) and hence in upregulation of ferritin L-chain synthesis. The disease is characterized by increased L-ferritin in serum and tissues and early onset of bilateral cataracts. Iron metabolism is normal, and there is no tissue iron overload. At least 25 nucleotide substitutions and deletions in the L-ferritin IRE have been described in families with HHCS, originating from diverse European, Australian and North American populations. We studied the molecular pathogenesis of HHCS in three unrelated kinderships of western Greek origin, with 19 affected members. We identified a relatively rare C39G mutation located in the hexanucleotide loop of L-ferritin IRE. Computational analysis of mRNA folding of mutant FTL IRE predicted that the C39 > G mutation leads to a rearrangement of base pairing in this critical region, which is likely to modify the IRP binding affinity. All subjects with HHCS were heterozygotes for the same C39G mutation. Clinical and laboratory phenotypes were described. Moreover, there was evidence of an association between this FTL IRE stem-loop mutation and very high ferritin levels. Our findings broaden the list of populations where HHCS has been described.
authors.affiliation: First Department of Internal Medicine, Athens University Medical School, "Laikon" General Hospital, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Papanikolaou
authors.forename: Helen
authors.initials: H
authors.lastname: Chandrinou
authors.forename: Evrydiki
authors.initials: E
authors.lastname: Bouzas
authors.forename: Despina
authors.initials: D
authors.lastname: Contopoulos-Ioannidis
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Kalotychou
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Prentzas
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Lilakos
authors.forename: Ioannis
authors.initials: I
authors.lastname: Asproudis
authors.forename: Danai
authors.initials: D
authors.lastname: Palaiologou
authors.forename: Evangelos
authors.initials: E
authors.lastname: Premetis
authors.forename: Ioannis
authors.initials: I
authors.lastname: Papassotiriou
authors.forename: Nikos
authors.initials: N
authors.lastname: Sakellaropoulos
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics* / Q000378:metabolism; D002386:Cataract / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005293:Ferritins / Q000096:biosynthesis / Q000235:genetics*; D005799:Genes, Dominant; D006115:Greece; D006801:Humans; D019189:Iron Metabolism Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009690:Nucleic Acid Conformation; D010375:Pedigree; D017354:Point Mutation; D013577:Syndrome
chemical_list: D020121:5' Untranslated Regions; D005293:Ferritins