After two decades of intensive research, the genetic complexity
of hereditary hemochromatosis is still unfolding. The majority
of hereditary hemochromatosis cases are due to C282Y
- The C282Y mutation, caused by a guanine to adenine
transition at nucleotide 845 (TGC—TAC), results in the
substitution of cysteine (C) by tyrosine (Y) at amino acid
position 282 in the HFE protein product.
- The C282Y mutation alters HFE protein structure,
disrupting its transport to and presentation on the cell
C282Y HFE Mutation
The C282Y mutation, caused by a guanine (G) to Adenine
(A) transition, results in the substitution of cysteine by
tyrosine in the HFE protein.
- The H63D mutation results in the substitution of histidine
(H) by aspartate (D) at amino acid position 63 in the HFE
- The H63D mutation does not appear to prevent cell-surface
expression, indicating that the C282Y mutation causes a
greater loss of protein function than does H63D.
Other HFE Gene Mutations
- In addition to C282Y and H63D, more than 10 other missense
mutations that cause amino acid substitutions have been
documented. A missense mutation indicates a change in DNA,
resulting in an amino acid substitution.
- In one, a substitution of cysteine (C) by serine (S) at
amino acid position 65 (S65C) is implicated in a very mild
form of hereditary hemochromatosis in rare instances.
- Other mutations have been described in HFE but most are
very low frequency.
- There may be HFE gene mutations that have yet to be
identified, or mutations in other iron-regulating genes that
have not been determined. Because of this, having a negative
genetic test does not rule out potential significant iron
overload or future risk of iron overload.
(Bomford A, 2002; Mura C, 1999; Pointon JJ, 2000;
Wallace DF, 2002; Waheed A, 1997)
Note: Amino acid substitutions are given with the standard
single-letter notation for amino acids: (tyrosine-Y, cysteine-C,
histidine-H, aspartate-D, senine-S) (Umek RM 2001)