title: [From gene to disease; HFE-mutations in primary haemochromatosis].
abstract: Primary haemochromatosis is an autosomal recessive disorder with a high prevalence (1 in 200-400) among North-Europeans. Approximately 64-100% of patients with primary haemochromatosis are homozygous for a missense mutation that alters a major-histocompatibility-complex class I-like protein designated HFE (from 'haemochromatosis'). This predominant mutation is a substitution of cysteine to tyrosine at amino acid residue 282 (Cys282Tyr) in the alpha 3-domain of the HFE protein. This mutation in the HFE protein in the intestinal crypt cells is supposed to lead to up-regulation of iron transporters for dietary iron in the mucosal cells at the tip of the duodenal villi. As a consequence, an excess of absorbed iron accumulates in the major organs of the HFE-mutated patients, leading to multi-organ dysfunction. A second mutation, His63Asp, in the HFE-gene is enriched in primary haemochromatosis patients who are concomitantly heterozygous for the Cys282Tyr-mutation. However, its role in the pathophysiology of primary haemochromatosis is not yet clear. A small subgroup of patients with primary haemochromatosis do not have mutations in HFE; for some of them the genetic basis has been determined. Homozygosity for the Cys282Tyr-mutation plus biochemical and clinical evidence of iron overload renders the diagnosis of HFE-related primary haemochromatosis indisputable. In other cases, liver biopsy remains the gold standard for the diagnosis of primary haemochromatosis. First-degree relatives of index patients should be screened for the disease.
authors.affiliation: Afd. Klinische Chemie, Universitair Medisch Centrum St Radboud, Postbus 9101, 6500 HB Nijmegen. d.swinkels@akc.umcn.nl
authors.forename: D W
authors.initials: DW
authors.lastname: Swinkels
authors.forename: E M G
authors.initials: EM
authors.lastname: Jacobs
mesh_terms: D019943:Amino Acid Substitution; D003545:Cysteine / Q000235:genetics; D005838:Genotype; D006432:Hemochromatosis / Q000175:diagnosis / Q000235:genetics*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D020125:Mutation, Missense; D014443:Tyrosine / Q000235:genetics
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014443:Tyrosine; D003545:Cysteine
vernacular_title: Van gen naar ziekte; HFE-mutaties bij primaire hemochromatose.