MOLECULAR-GENETICS OF HEMOCHROMATOSIS

Haemochromatosis is an inherited disorder of iron metabolism character ized by a general iron over loading. Without diagnosis and early treat ment, it is a serious and potentially fatal disease by cardiac failure or hepatocellular carcinoma in particular. Gene prevalence was estima ted at 0.06 in Brittany, so that haemochromatosis may be the most comm on genetic disease in this area. The biochemical defect of the disease is unknown; only one fact is well established: the iron absorption th rough duodenal mucosa is excessive. However we don't know if it is a p rimary event. The gene is also unknown but in 1975 it was located on t he short arm of chromosome 6, closely linked to the HLA class I region , less than 1 cM from HLA-A. None of the genes coding for the known ir on proteins could be the haemochromatosis gene because of their chromo somal localization. In order to locate this gene with precision, we ha ve used a reverse genetic approach now called positional cloning. Char acterization of new polymorphic markers and linkage disequilibrium ana lysis, have led us to locate the gene within a 350 kb region around HL A-A. We have then searched for all the structural genes in this region . Seven new genes have been so identified and located with precision. A structural analysis of these genes was undertaken to find an eventua l abnormality in patients.