MUTATIONS IN THE MHC CLASS I-LIKE CANDIDATE GENE FOR HEMOCHROMATOSIS IN FRENCH PATIENTS

A candidate gene for hemochromatosis has recently been localized on th e short arm of chromosome 6, about 4 megabases telomeric to the major histocompatibility complex. It encodes a protein that exhibits signifi cant similarity to the HLA class I molecules and can be provisionally designated HLA-hc. Genotype analysis of 94 hemochromatosis patients li ving in France and a similar number of controls confirms that the dise ase is strongly associated with homozygosity at nucleotide 845 (72% of the patients and none of the controls carry two copies of the 845A va riant). The data are consistent with hemochromatosis being a heterogen eous disease: about 79% of the cases in this sample would be caused by a defect in HLA-he and 21% by an unrelated mechanism. A second varian t (187 G) enriched on patient chromosomes that do not carry the 845A m utation might influence the affinity of a ligand for HLA-hc; the exact nature of this ligand remains to be discovered. The 845A variant is t he best genetic marker for the disease identified to date, and the det ection of 845A homozygosity should now permit diagnosis of a readily c urable disease and the prevention of sometimes deadly complications in at least 72% of the patients.