MOLECULAR-GENETICS OF HEMOCHROMATOSIS

Molecular genetics of hemochromatosis. - Haemochromatosis is an inheri ted disorder of iron metabolism characterized by a general iron over l oading. Without diagnosis and early treatment, it is a serious and pot entially fatal disease by cardiac failure or hepatocellular carcinoma in particular. Gene prevalence was estimated at 0.06 in Brittany, so t hat haemochromatosis may be the most common genetic disease in this ar ea. The biochemical defect of the disease is unknown; only one fact is well established: the iron absorption through duodenal mucosa is exce ssive. However we don't know if it is a primary event. The gene is als o unknown but in 1975 it was located on the 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 iron proteins could be the haem ochromatosis gene because of their chromosomal localization. In order to locate this gene with precision, we have used a reverse genetic app roach now called positional cloning. Characterization of new polymorph ic markers and linkage disequilibrium analysis have led us to locate t he gene within a 350 kb region around HLA-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 eventual abnormality in patients.