Cysteine to tyrosine substitution at position 282 (p.C282Y)

Plasma membrane

Figure 12.10 Schematic of HFE protein. Hypothetical model of HLA-H protein based on similarity to MHC class I proteins as proposed by Feder et al. with the positions of the mutations they identified shown. Redrawn and reprinted by permission from Macmillan Publishers Ltd: Nature Genetics (Feder et al. 1996), copyright 1996.

Box 12.11 Lessons from murine studies of HFE

The HFE gene in mice is structurally identical to that in humans (Riegert et al. 1998). This has allowed both knock-out studies and analysis of the effects of specific mutations. HFE knock-out mice show impaired iron homeostasis with elevated transfer-rin saturations and hepatic iron loading (Zhou et al.

1998). Iron overloading mimicking human haemo-chromatosis was seen in knock-in mice homozygous for the C282Y mutation: the effects of the mutation were not, however, to produce a null allele (in other words to give no gene product or product activity) (Levy et al. 1999).

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