title: Iron overload in HFE C282Y heterozygotes at first genetic testing: a strategy for identifying rare HFE variants.
abstract: BACKGROUND
  Heterozygotes for the p.Cys282Tyr (C282Y) mutation of the HFE gene do not usually express a hemochromatosis phenotype. Apart from the compound heterozygous state for C282Y and the widespread p.His63Asp (H63D) variant allele, other rare HFE mutations can be found in trans on chromosome 6.
  
  
  METHODS
  We performed molecular investigation of the genes implicated in hereditary hemochromatosis in six patients who presented with iron overload but were simple heterozygotes for the HFE C282Y mutation at first genetic testing. Functional impairment of new variants was deduced from computational methods including molecular modeling studies.
  
  
  RESULTS
  We identified four rare HFE mutant alleles, three of which have not been previously described. One mutation is a 13-nucleotide deletion in exon 6 (c.1022_1034del13, p.His341_Ala345 > LeufsX119), which is predicted to lead to an elongated and unstable protein. The second one is a substitution of the last nucleotide of exon 2 (c.340G > A, p.Glu114Lys) which modifies the relative solvent accessibility in a loop interface. The third mutation, p.Arg67Cys, also lies in exon 2 and introduces a destabilization of the secondary structure within a loop of the α1 domain. We also found the previously reported c.548T > C (p.Leu183Pro) missense mutation in exon 3. No other known iron genes were mutated. We present an algorithm at the clinical and genetic levels for identifying patients deserving further investigation. Conclusions Our results suggest that additional mutations in HFE may have a clinical impact in C282Y carriers. In conjunction with results from previously described cases we conclude that an elevated transferrin saturation level and elevated hepatic iron index should indicate the utility of searching for further HFE mutations in C282Y heterozygotes prior to other iron gene studies.
authors.affiliation: Laboratoire d'Hématologie, CHU de Montpellier, Montpellier, France. p-martinez@chu-montpellier.fr
authors.forename: Patricia
authors.initials: P
authors.lastname: Aguilar-Martinez
authors.forename: Bernard
authors.initials: B
authors.lastname: Grandchamp
authors.forename: Séverine
authors.initials: S
authors.lastname: Cunat
authors.forename: Estelle
authors.initials: E
authors.lastname: Cadet
authors.forename: François
authors.initials: F
authors.lastname: Blanc
authors.forename: Marlène
authors.initials: M
authors.lastname: Nourrit
authors.forename: Kaiss
authors.initials: K
authors.lastname: Lassoued
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Schved
authors.forename: Jacques
authors.initials: J
authors.lastname: Rochette
mesh_terms: D000328:Adult; D000483:Alleles; D005260:Female; D005293:Ferritins / Q000097:blood; D023061:Gene Order; D005820:Genetic Testing; D014644:Genetic Variation; D006432:Hemochromatosis / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D000071020:Hemochromatosis Protein; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D019190:Iron Overload / Q000150:complications* / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D005293:Ferritins