title: A new missense mutation in the L ferritin coding sequence associated with elevated levels of glycosylated ferritin in serum and absence of iron overload.
abstract: 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.
  
  
  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 mumol/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" alpha helix.
authors.affiliation: AP-HP, Service de Génétique et Biochimie hormonale, Hôpital Bichat Claude Bernard, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kannengiesser
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Jouanolle
authors.forename: Gilles
authors.initials: G
authors.lastname: Hetet
authors.forename: Annick
authors.initials: A
authors.lastname: Mosser
authors.forename: Françoise
authors.initials: F
authors.lastname: Muzeau
authors.forename: Dominique
authors.initials: D
authors.lastname: Henry
authors.forename: Edouard
authors.initials: E
authors.lastname: Bardou-Jacquet
authors.forename: Martine
authors.initials: M
authors.lastname: Mornet
authors.forename: Pierre
authors.initials: P
authors.lastname: Brissot
authors.forename: Yves
authors.initials: Y
authors.lastname: Deugnier
authors.forename: Bernard
authors.initials: B
authors.lastname: Grandchamp
authors.forename: Carole
authors.initials: C
authors.lastname: Beaumont
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D001052:Apoferritins; D002648:Child; D005192:Family Health; D005260:Female; D005293:Ferritins / Q000097:blood* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006031:Glycosylation; D006579:Heterozygote; D006801:Humans; D019190:Iron Overload / Q000097:blood* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D017433:Protein Structure, Secondary; D055815:Young Adult
chemical_list: C507433:FTL protein, human; D005293:Ferritins; D001052:Apoferritins