title: DMT1 genetic variability is not responsible for phenotype variability in hereditary hemochromatosis.
abstract: OBJECTIVE
  Homozygosity for a cysteine to tyrosine translocation at position 282 within the HFE gene (C282Y) is responsible for over 90% of hereditary hemochromatosis (HH) in Celtic populations. Determining those C282Y homozygotes at greatest risk for iron overload is a major clinical concern as only a small percentage will develop clinically significant iron overload. Divalent metal transport protein (DMT1) on the apical surface of duodenal enterocytes is recognised as the major iron import protein. We investigated whether genetic variability within the DMT1 gene may partly explain the phenotypic variability seen amongst a group of C282Y homozygotes with iron overload.
  
  
  METHODS
  One hundred and one unrelated C282Y homozygotes and 103 C282Y negative controls were analysed for the presence of four specific mutations/polymorphisms within the DMT1 gene (1245T/C, 1303C/A, IVS4 + 44C/A, IVS15Ex16-16C/G) using standard PCR techniques. Hepatic iron deposition was determined in 32 HH patients following Perls Prussian blue staining (0-4+). Estimations of the haplotype frequencies were performed utilising the program Arlequin version 2.
  
  
  RESULTS
  There were no significant differences in the allele frequencies of the IVS4 + 44C/A, 1303C/A, 1254T/C and IVS15Ex16-16C/G polymorphisms in the patient cohort compared to those observed in the control cohort. The commonest haplotypes identified were CCTC: IVS4C + 44C, 1303C, 1254T, IVS15ex16-16C; ACCC: IVS4C + 44A, 1303C, 1254C, IVS15ex16-16C and ACTG: IVS4C + 44A, 1303C, 1254T, IVS15ex16-16G. Similarly, there were no significant differences in the frequencies of these three haplotypes in the patient cohorts (regardless of the degree of hepatic iron deposition) compared to the control cohort.
  
  
  CONCLUSIONS
  Polymorphisms within DMT1 gene do not influence penetrance of the HH phenotype.
authors.affiliation: Centre for Liver Disease, Mater Misericordiae University Hospital, Dublin 7, Ireland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kelleher
authors.forename: Eleanor
authors.initials: E
authors.lastname: Ryan
authors.forename: Sharon
authors.initials: S
authors.lastname: Barrett
authors.forename: Conor
authors.initials: C
authors.lastname: O'Keane
authors.forename: John
authors.initials: J
authors.lastname: Crowe
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006432:Hemochromatosis / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000235:genetics; D033862:Iron-Binding Proteins / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D007501:Iron; D033862:Iron-Binding Proteins; D000099236:Solute Carrier Family 11, Member 2