The gene for hereditary haemochromatosis (HFE) lies telomeric to HLA-A and is believed to be expressed in the intestinal mucosa. Its product has not been characterized, but iron overload and its pathological consequences occur only in homozygotes for this putative gene. The genes encoding the putative human counterparts of the mouse thymus-leukaemia (TL) antigens map to the area where the HFE gene lies. Here, we postulate that a human TL gene may encode a protein acting as or interacting with the transferrin (Tf) receptor in the intestinal mucosa. This hypothesis is based on the following observations: (i) hereditary haemochromatosis (HH) is due to excessive absorption of iron through the intestinal mucosa. HH has a strong association with HLA-A3, but HLA-A3 has no direct role in the pathogenesis and reflects linkage disequilibrium with a telomeric gene. (ii) An HLA-A3 homozygous genotype is associated with the highest relative risks for both early-onset leukaemia and HH. In analogy to the susceptibility locus in mice, this genotype may reflect a TL gene association in leukaemia and raise the possibility of a TL gene involvement in HH. (iii) A TL antigen-like human molecule encoded in the region telomeric to HLA-A, TCA, is expressed in leukaemia and recognized by a Tf receptor-specific monoclonal antibody. The Tf receptor is believed to have a role in the control of intestinal iron absorption. (iv) In mice, particular TL antigens are exclusively expressed in the intestinal mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)