PREDOMINANCE OF THE HLA-H CYS282TYR MUTATION IN AUSTRIAN PATIENTS WITH GENETIC HEMOCHROMATOSIS

Background/Aims: Genetic haemochromatosis is the most common autosomal recessive disorder in Northern European populations, A major histocom patibility complex class I-like gene, HLA-H, has been proposed to be r esponsible for genetic haemochromatosis. The prevalence of HLA-H gene mutations 282(TGC; Cys/TAC; Tyr) and 63(CAT; His/GAT; Asp) was determi ned in patients of Austrian origin. Methods: DNA extracted from the bl ood of 40 Austrian patients and 271 controls was used to amplify HLA-H gene fragments by the polymerase chain reaction method, The base chan ges responsible for mutations Cys282Tyr and His63Asp alter recognition sites for restriction enzymes SnaB I and Bc1 I, respectively, Digesti on products were separated by agarose gel electrophoresis and visualis ed by ethidium bromide staining. Results: Thirty-one (77.5%) genetic h aemochromatosis patients were homozygous for mutation Cys282Tyr and th ree compound heterozygous for mutations Cys282Tyr and His63Asp. One pa tient was homozygous for mutation His63Asp but normal for mutation Cys 282Tyr, Four patients were normal at both genetic loci and one patient was heterozygous for mutation His63Asp. One control subject homozygou s for mutation Cys282Tyr was found on investigation to fulfil diagnost ic criteria for haemochromatosis, Eight control subjects homozygous fo r mutation His63Asp showed no biochemical or clinical evidence of haem ochromatosis indicating that this variant is not directly responsible for haemochromatosis, Absence of the Cys282Tyr mutation in six genetic haemochromatosis patients with distinct haplotypes indicates mutation s within the HLA-H gene or at alternative genetic loci are the cause o f genetic haemochromatosis in these patients. Conclusions: The HLA-H C ys282Tyr defect is likely to play a key role in the pathogenesis of ha emochromatosis in most patients, Predominance of a single HLA-H gene m utation in haemochromatosis allows presymptomatic screening by genotyp ic analysis.