[Hereditary hemochromatosis--new developments after discovery of the HFE gene].
Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism, resulting in an increased iron deposition and multiorgan failure. Recently a candidate gene of HH, termed HFE, has been identified on chromosome 6, coding for a protein homologous to major histocompatibility complex (MHC) class I molecules. Two mutations of the hemochromatosis gene leading to an exchange of cysteine to tyrosine at aminoacid 282 and histidine to asparagine at aminoacid 63, are retained responsible for the development of hereditary hemochromatosis. The Cys282Tyr-mutation disrupts a disulfid bond and thus abrogates binding of the mutant HFE-protein to beta 2-microglobulin and its presentation on the cell surface. The His63Asp-mutation seems to play a role in pH-regulated dissociation of the transferrin receptor/transferrin complex in the lysosome. Mutations of the HFE-protein alter the affinity of the transferrin receptor for its ligand transferrin and may thus cause an intracellular accumulation of iron. Knowledge of the responsible gene allows a molecular diagnosis of HH. The new genetic marker can be used for screening and confirmation of HH reducing the need for confirmatory liver biopsies. Compared to standard screening parameters like ferritin and transferrin saturation genetic testing will allow the diagnosis of HH in an early, asymptomatic state before iron accumulation has occurred. As a normal life expectancy of patients with HH can be achieved if iron reduction is initiated early, genetic testing may thus be of great benefit for patients with HH.
Erhardt
A
A
Klinik für Gastroenterologie, Hepatologie und Infektiologie, Heinrich-Heine-Universität Düsseldorf.
Niederau
C
C
Osman
Y
Y
Häussinger
D
D
D000465:Algorithms; D019943:Amino Acid Substitution / Q000235:genetics; D001706:Biopsy; D002869:Chromosome Aberrations / Q000235:genetics; D025063:Chromosome Disorders; D005808:Genes, Recessive / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D006680:HLA Antigens / Q000235:genetics*; D006432:Hemochromatosis / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000473:pathology; D008565:Membrane Proteins
D005819:Genetic Markers; C103673:HFE protein, human; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins