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Hereditary Hemochromatosis
Determination of the mutation C282Y and the
predisposing allel H63D in the hemochromatosis (Hfe) gene
RDB2045
CLINICAL RELEVANCE
Hereditary hemochromatosis is an autosomal recessively hereditary
disorder of intestinal iron absorption. The disease has a prevalence
of approx. 0.3-0.5% (1) in Caucasians, and is thus the most frequent
hereditary disease in Europe.
The increased iron absorption causes iron to be deposited in various
organs. This can, among other things, lead to cirrhosis of the liver,
diabetes mellitus, hypogonadism and cardiac failure.
In 1996, Feder et al. were able for the first time to draw a connection
between mutations in a hemochromatosis gene (3) and hereditary hemochromatosis.
The Hfe gene encodes a protein similar in structure to the MHC class
1 molecules (4). Also, owing to its physical proximity to the HLA
genes, it was originally termed as an HLA-H gene. The protein encoded
by the Hfe gene interacts with the transferrine receptor and is involved
in the regulation of iron absorption (5).
Feder et al. (3) found two point mutations which could repeatedly
be found in patients with hereditary hemochromatosis. The replacement
of G (guanine) by A (adenine) at position 845 in the Hfe gene causes
in the protein a change from cysteine (C) to tyrosine (Y) at the amino
acid position 282 (mutation C282Y). A mutation at position 187 leads
to the substitution of C (cytosine) by G, and therefore to a change
in the protein at position 63 from histidine (H) to asparaginic acid
(D) (mutation H63D).
The clear association between the C282Y mutation and hereditary hemochromatosis
has been proved in numerous studies. This mutation occurs heterozygously
in approx. 5% of the total population (6). Over 90% of all patients
with hemochromatosis carry the allele C282Y homozygously (1,6,7).
The association between the mutation H63D and hereditary hemochromatosis
is much less clear. The mutated allele is widespread and occurs heterozygously
in approx. 20% of the population (6,8). The homozygous presence of
the mutation H63D does not cause a predisposition for hereditary hemochromatosis.
However, the few patients suffering from hemochromatosis who have
the mutation C282Y in heterozygous form also have very frequently
the mutation H63D (1,3,7).
Owing to their physical proximity in the Hfe gene, both mutations
have never been found simultaneously on one chromosome (6). This means
that patients who are homozygous for the C282Y mutation are always
negative for the H63D mutation and vice versa.
The detection of the specific mutations in the Hfe gene is a important
diagnostic, because the disease does not reduce life expectancy if
it is diagnosed and treated at an early stage.
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Literature
(1)
Merryweather-Clarke AT, Pointon JJ, Shearman JD ... (1997)
Global prevalence of putative hemochromatosis gene mutations
J Med Genet 34: 275-278
(2)
Schettler G und Greten H (1998)
Innere Medizin
Thieme Verlag Stuttgart, 9. Auflage: 875-877
(3)
Feder JN, Gnirke A, Thomas W ... (1996)
A novel MHC class 1-like gene is mutated in patients with hereditary
hemochromatosis
Nat Genet, 13: 399-408
(4)
Lebron JA, Bennett MJ, Vaughn DE ... (1998)
Crystal structure of the hemochromatosis protein HFE and characterization
of its interaction with transferrin receptor
Cell, 93: 111-123
(5)
Feder JN, Penny DM, Irrinki A ... (1998)
The hemochromatosis gene product complexes with the transferrin receptor
and lowers its affinity for ligand binding
Proc Natl Acad Sci USA, 95: 1472-1477
(6)
Gottschalk R, Seidl C, Löffler T ... (1998)
HFE codon 63/282 (H63D/C282Y) dimorphism in German patients with genetic
hemochromatosis
Tissue Antigens 51: 270-275 |
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