When Dr John Sheldon published his classic monograph on hemochromatosis in 1935, he documented the evidence, both from the literature and from his own practice, that such patients were suffering from an inherited disorder of iron metabolism, but he could hardly have anticipated the remarkable developments of the next 60 years. These developments were the outcome of continued, detailed basic and clinical observations by investigators who were able to exploit the major technological advances in laboratory research to probe the cytopathologic, biochemical and, ultimately, the molecular basis of one of the most common human genetic disorders.

It was the landmark discovery in the 1970s by Dr Marcel Simon and his colleagues in Brittany, France that clearly established the autosomal recessive inheritance of hemochromatosis and its close linkage with the major histocompatibility class I complex A3 on the short arm of chromosome. Subsequent confirmation of this finding by investigators scattered throughout the world documented a prevalence of homozygotes with hemochromatosis of between 1 in 250 and 1 in 300 of the Caucasian population, and a phenotypic expression that was virtually invariable in individuals possessing the abnormal allele on both chromosomes. With all the evidence pointing to the relentless accumulation of body iron in such individuals during the formative evolution of their disease, the search for the abnormal gene became an imperative of the highest priority.