Genetics of Hemochromatosis

The gene identified by Feder and colleagues (1996) ("HLA-H" but now defined as HFE) lies approximately 5Mb telomeric to HLA-A and shows similarity to MHC class 1 genes. A single mutation is associated with HHC in 65 to 100 percent of cases.

The mutation is a G to A transition at nucleotide 845 and results in the substitution of cysteine with tyrosine at position 282 (C282Y) and disruption of a disulphide bridge required to stabilise the protein. A second mutation, a C to G change causing a histidine to aspartic acid substitution at position 63 (H63D) was also identified.

Recent data from numerous countries have confirmed that the C282Y mutation is primarily responsible for the large majority of HLA-linked HHC cases. The figures range from approximately 95 percent in Australia to 90 percent in Great Britain, 80 percent in the United States to 60 percent in Italy. The higher values are found in populations of Northern European extraction, the lower percentage in patients of Southern European (Mediterranean) extraction. (Jazwinska et al, 1996; Carella et al, 1996). Thus it must be emphasised that a varying proportion (10 to 40 percent) do not carry either mutation, and clinicians should not be misled into believing that patients who are not homozygous for the C282Y mutation do not have HHC. A small proportion (approximately 7 percent) of HHC cases are compound heterozygotes (i.e., carrying one copy of each of the C282Y and H63D mutations). Non-HFE-associated familial haemochromatosis has been described recently from Italy (Carella et al, 1997) and it is now established that the juvenile form of haemochromatosis, while clinically closely resembling the adult form, but occurring in the second and third decades of life, is not due to this mutation; nor are African iron overload or neonatal haemochromatosis.

There is emerging clinical evidence to suggest that the second mutation (H63D) has a significant independent role in causing iron overload although this is usually of mild to moderate degree. Thus, compound (C282Y/H63D) heterozygotes may develop iron overload of a degree previously recognised as consistent with homozygous HLA-associated HHC, although as a group they do not have as severe iron overload as C282Y homozygotes (Crawford et al, 1998). The H63D mutation appears to have both low penetrance and comparatively low expressivity.