title: Frequency of the S65C mutation of HFE and iron overload in 309 subjects heterozygous for C282Y.
abstract: OBJECTIVE
  HFE-related haemochromatosis is a common disorder of iron metabolism. Most affected individuals are homozygous for the C282Y mutation of HFE. Some are compound heterozygotes for C282Y/H63D. A small proportion have neither of these genotypes. We have investigated the phenotype of compound heterozygotes for C282Y and another missense mutation S65C.
  
  
  METHODS
  Genotype for the S65C mutation was determined in 309 subjects heterozygous for C282Y and negative for H63D, referred because of increased serum iron indices or family screening. A control sample comprising 315 individuals was also studied.
  
  
  RESULTS
  Twelve individuals were compound heterozygotes for C282Y and S65C. Seven, referred for family screening, had normal serum iron indices. Five subjects had elevated serum iron indices; three of these had elevated hepatic iron and have received treatment for iron overload. Transferrin saturation was significantly elevated in C282Y/S65C compound heterozygotes compared with simple C282Y heterozygotes.
  
  
  CONCLUSIONS
  Some C282Y/S65C compound heterozygotes have elevated serum iron indices and iron overload. The penetrance of this genotype is low and other genetic and environmental factors may influence the expression of iron loading. Screening for S65C may be useful in individuals with iron overload who are not homozygous for C282Y or compound heterozygous for C282Y/H63D.
authors.affiliation: Centre for Hepatology, Department of Medicine, Royal Free and University College Medical School, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Wallace
authors.forename: Ann P
authors.initials: AP
authors.lastname: Walker
authors.forename: Antonello
authors.initials: A
authors.lastname: Pietrangelo
authors.forename: Michael
authors.initials: M
authors.lastname: Clare
authors.forename: Adrian B
authors.initials: AB
authors.lastname: Bomford
authors.forename: Jeannette L
authors.initials: JL
authors.lastname: Dixon
authors.forename: Lawrie W
authors.initials: LW
authors.lastname: Powell
authors.forename: V Nathan
authors.initials: VN
authors.lastname: Subramaniam
authors.forename: James S
authors.initials: JS
authors.lastname: Dooley
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D005260:Female; D005787:Gene Frequency; D006680:HLA Antigens / Q000235:genetics*; D000071020:Hemochromatosis Protein; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000097:blood / Q000378:metabolism; D019190:Iron Overload / Q000097:blood / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D014168:Transferrin / Q000378:metabolism
chemical_list: C103673:HFE protein, human; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014168:Transferrin; D007501:Iron