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 co
nsequences occur only in homozygotes for this putative gene. The genes
encoding the putative human counterparts of the mouse thymus-leukaemi
a (TL) antigens map to the area where the HFE gene lies. Here, we post
ulate that a human TL gene may encode a protein acting as or interacti
ng with the transferrin (Tf) receptor in the intestinal mucosa. This h
ypothesis is based on the following observations: (i) hereditary haemo
chromatosis (HH) is due to excessive absorption of iron through the in
testinal mucosa. HH has a strong association with HLA-A3, but HLA-A3 h
as no direct role in the pathogenesis and reflects linkage disequilibr
ium with a telomeric gene. (ii) An HLA-A3 homozygous genotype is assoc
iated with the highest relative risks for both early-onset leukaemia a
nd HH. In analogy to the susceptibility locus in mice, this genotype m
ay reflect a TL gene association in leukaemia and raise the possibilit
y of a TL gene involvement in HH. (iii) A TL antigen-like human molecu
le encoded in the region telomeric to HLA-A, TCA, is expressed in leuk
aemia and recognized by a Tf receptor-specific monoclonal antibody. Th
e 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. Therefore, an HLA-A3-linked TL-lik
e molecule, expressed in the intestinal mucosa and sharing a structura
l similarity with the Tf receptor, may be the yet unknown product of H
FE.