title: Predominance of the HLA-H Cys282Tyr mutation in Austrian patients with genetic haemochromatosis.
abstract: OBJECTIVE
  Genetic haemochromatosis is the most common autosomal recessive disorder in Northern European populations. A major histocompatibility complex class I-like gene, HLA-H, has been proposed to be responsible for genetic haemochromatosis. The prevalence of HLA-H gene mutations 282(TGC; Cys/TAC; Tyr) and 63(CAT; His/GAT; Asp) was determined in patients of Austrian origin.
  
  
  METHODS
  DNA extracted from the blood of 40 Austrian patients and 271 controls was used to amplify HLA-H gene fragments by the polymerase chain reaction method. The base changes responsible for mutations Cys282Tyr and His63Asp alter recognition sites for restriction enzymes SnaB I and Bcl I, respectively. Digestion products were separated by agarose gel electrophoresis and visualised by ethidium bromide staining.
  
  
  RESULTS
  Thirty-one (77.5%) genetic haemochromatosis patients were homozygous for mutation Cys282Tyr and three compound heterozygous for mutations Cys282Tyr and His63Asp. One patient was homozygous for mutation His63Asp but normal for mutation Cys282Tyr. Four patients were normal at both genetic loci and one patient was heterozygous for mutation His63Asp. One control subject homozygous for mutation Cys282Tyr was found on investigation to fulfill diagnostic criteria for haemochromatosis. Eight control subjects homozygous for mutation His63Asp showed no biochemical or clinical evidence of haemochromatosis indicating that this variant is not directly responsible for haemochromatosis. Absence of the Cys282Tyr mutation in six genetic haemochromatosis patients with distinct haplotypes indicates mutations within the HLA-H gene or at alternative genetic loci are the cause of genetic haemochromatosis in these patients.
  
  
  CONCLUSIONS
  The HLA-H Cys282Tyr defect is likely to play a key role in the pathogenesis of haemochromatosis in most patients. Predominance of a single HLA-H gene mutation in haemochromatosis allows presymptomatic screening by genotypic analysis.
authors.affiliation: Department of Medicine, LKA Salzburg, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Datz
authors.forename: M R
authors.initials: MR
authors.lastname: Lalloz
authors.forename: W
authors.initials: W
authors.lastname: Vogel
authors.forename: I
authors.initials: I
authors.lastname: Graziadei
authors.forename: F
authors.initials: F
authors.lastname: Hackl
authors.forename: G
authors.initials: G
authors.lastname: Vautier
authors.forename: D M
authors.initials: DM
authors.lastname: Layton
authors.forename: T
authors.initials: T
authors.lastname: Maier-Dobersberger
authors.forename: P
authors.initials: P
authors.lastname: Ferenci
authors.forename: E
authors.initials: E
authors.lastname: Penner
authors.forename: F
authors.initials: F
authors.lastname: Sandhofer
authors.forename: A
authors.initials: A
authors.lastname: Bomford
authors.forename: B
authors.initials: B
authors.lastname: Paulweber
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006432:Hemochromatosis / Q000235:genetics*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic
chemical_list: C103673:HFE protein, human; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins