Hemochromatosis is a recessive disorder of iron metabolism characterized by
progressive iron lending of parenchymal organs which accounts for clinical
complications such as cirrhosis, diabetes mellitus, cardiopathy, endocrine
dysfunctions and arthropathy. Clinical complications which usually develop
after the third or fourth decade of life, can be fatal brat may be prevent
ed by phlebotomy if iron excess is detected at a very early stage.
The hemochromatosis gene (HFE) located 4.5 megabases telomeric to the HLA-A
locus encodes an HLA class I like protein and two missense mutations, C282
Y and H63D in complete disequilibrium have been identified within this gene
. Due to its high frequency in the general population, the involvement of H
63D in the pathogenesis of the disease remains controversial, and it might
correspond to a minor mutation. Conversely, the C282Y mutation is tightly l
inked to the disease, as it accounts for 80 to 100% of the hemochromatosis
eases in Northern Europe. The lower frequency observed in the patients in I
taly and South of France led to imagine either the implication of other mut
ations or of other genes. The C282Y mutation is absent in Asia and Africa a
nd is present in the general population with a decreasing gradient of frequ
ency from Northern to Southern Europe.
The prevalence of the disease was usually estimated to be 3% but the observ
ed frequency of the C282Y homozygotes is 5% in oar breton population raisin
g the question of the penetrance of the disease and consequently the use of
the genotypic test for its systematic screening.
As HFE encodes a membrane protein similar to HLA class I protein, its contr
ibution to iron overload is not obvious. The normal protein is predieted to
to be expressed at the cell surface in association with beta 2-microglobul
in, a localization for which C282Y is critical as it disrupts this associat
ion. This protein has also been shown to form a stable complex with the tra
nsferrin receptor leading to a decreased affinity for transferrin. A better
knowledge of its function will help to decipher iron and different metal-i
ons metabolism.
Although the exact role of the HFE protein is unknown, the genotypic test a
llows the clinicians to ascertain their diagnosis and genetic counselling.