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Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 9-11
The C282Y Mutation Causing Hereditary Hemochromatosis Does Not
Produce a Null Allele
By
Joanne E. Levy,
Lynne K. Montross,
Dena E. Cohen,
Mark D. Fleming, and
Nancy C. Andrews
From the Division of Hematology/Oncology, Children's Hospital;
Howard Hughes Medical Institute; the Division of Hematology and the
Department of Pathology, Brigham and Women's Hospital;
Program in Biological and Biomedical Sciences; and the Departments of
Medicine and Pediatrics, Harvard Medical School, Boston, MA.
 |
ABSTRACT |
Targeted mutagenesis was used to produce two mutations in the murine
hemochromatosis gene (Hfe) locus. The first mutation deletes a
large portion of the coding sequence, generating a null allele. The
second mutation introduces a missense mutation (C282Y) into the
Hfe locus, but otherwise leaves the gene intact. This mutation
is identical to the disease-causing mutation in patients with
hereditary hemochromatosis. Mice carrying each of the two mutations
were bred and analyzed. Homozygosity for either mutation results in
postnatal iron loading. The effects of the null mutation are more
severe than the effects of the C282Y mutation. Mice heterozygous for
either mutation accumulate more iron than normal controls. Interestingly, although liver iron stores are greatly increased, splenic iron is decreased. We conclude that the C282Y mutation does not
result in a null allele.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
HEREDITARY HEMOCHROMATOSIS is a common,
autosomal recessive disorder affecting approximately one million people
in the United States. The gene responsible for most cases was
identified by positional cloning in 1996.1 Termed
HFE, it encodes an atypical member of the class I major
histocompatibility protein family that heterodimerizes with
 2-microglobulin. Most affected patients are homozygous for a unique
missense mutation that results in a tyrosine for cysteine substitution
at amino acid 282 (C282Y).1 It is not clear whether
heterozygosity for the C282Y mutation, by itself, can predispose to
iron overload. The C282Y mutation disrupts an intramolecular disulfide
bond, and may interfere with 2-microglobulin binding.2
Mice deficient in 2-microglobulin and mice deficient in Hfe both
develop systemic iron overload.3,4 The function of HFE and
its role in iron metabolism remain unknown. We created two mutant mouse
strains to investigate whether the C282Y mutation results in total loss
of protein function, and to develop a model system to study the
pathogenesis of hemochromatosis.
| |
MATERIALS AND METHODS |
The murine Hfe gene resembles its human ortholog. Codon 282 is
49 nucleotides upstream of an exon-intron junction. We used site-directed mutagenesis (QuikChange kit; Stratagene, La Jolla, CA) to
introduce the C282Y mutation into murine codon 282. Genomic Hfe
DNA was inserted into the pTKLNCL targeting vector (from R. Mortenson,
Brigham and Women's Hospital), such that the C282Y mutation was close
to the neomycin resistance cassette (Fig
1). The construct was electroporated into
TC-1 embryonic stem (ES) cells,5 and recombinant clones
were selected as previously described.6 We anticipated that
most targeting events would involve recombination between homologous
sequences located further from the selectable marker than the site of
the mutation and would, therefore, result in introduction of the C282Y
mutation into the mouse genome. This proved to be true. Targeting
vector sequences were located within an intron, between loxP sites. A
second targeting vector was similarly used to construct an Hfe
null allele (Fig 1).
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| Fig 1.
Targeting constructs used to create mutant Hfe
alleles. The structures of the two targeting constructs are shown, with
reference to the murine Hfe locus. In each case, the
intron/exon structure of the genomic clone is shown on the top line,
the structure of the targeting construct is shown on the second line,
and the structure of the correctly targeted mutant locus is shown on
the third line. Black boxes are Hfe exons. Translational start
(ATG) and stop (STOP) sites are indicated. 5' homology (5' hom) and 3'
homology (3' hom) regions are indicated for each targeting vector. The
locations of the neomycin resistance (NEO) and cytosine deaminase (CD)
cassettes are shown. Hatched boxes represent loxP sites. The asterisk
(*) shows the site of codon 282. (a) Summarizes the strategy used to
make the null allele; (b) summarizes the strategy used to introduce the
C282Y missense mutation. The final line in (b) shows the structure of
the C282Y allele after vector sequences have been removed by
Cre-mediated recombination between loxP sites.
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Correctly targeted ES cell clones were injected into mouse blastocysts
to generate chimeric mice carrying each mutant allele. Inbred mouse
strains vary markedly in parameters of iron metabolism7 (and our unpublished data). For this reason, the original
chimeric mice were bred to two different inbred strains. First, they
were bred to 129/SvEvTac mice from which the TC-1 ES cell line was derived,5 to place the mutations on an inbred background.
Because 129 mice load iron to a greater extent than many other strains (unpublished data), first-generation chimeric mice were also bred to
C57BL/6J mice, to place each mutation on a mixed C57BL/6J × 129/SvEvTac background. Vector sequences were subsequently
removed from the Hfe locus carrying the C282Y mutation by
breeding to 129/SvEvTac mice expressing Cre recombinase.8
This maneuver deleted vector sequences in the germline, leaving only a
single loxP site within the intron. Reverse transcriptase-polymerase chain reaction analysis of mRNA confirmed that the C282Y allele was
expressed and produced a properly spliced mRNA (data not shown).
Animals were maintained on standard mouse diet and iron status was
evaluated at various ages as previously
described.6
| |
RESULTS AND DISCUSSION |
As shown in Fig 2, genotype correlated
strongly with iron loading. Mice heterozygous for either mutant allele
showed more iron loading than wild-type mice of the same genetic
background (Fig 2a). Similar to previously reported
results,4 mice homozygous for the null allele developed
massive iron loading early in life. This occurred postnatally;
wild-type and mutant iron levels were identical at 3 days of age, and
iron loading occurred more rapidly on the 129/SvEvTac background (data
not shown). C282Y homozygotes had a phenotype intermediate between null
homozygotes and wild-type mice. Results were confirmed by Prussian blue
staining of liver tissue (Fig 2b). These results indicate that the
C282Y mutation does not completely disrupt the function of Hfe, and is
not a null mutation. Interestingly, mice began to accumulate hepatic iron before circulating transferrin was fully saturated. At 4 weeks of
age, on the 129/SvEvTac background, nonfasting transferrin saturations
were 84.0 ± 1.1, 89.5 ± 1.3, and 88.3 ± 1.4 for wild type, C282Y
homozygotes, and null homozygotes, respectively. These blood samples
were obtained by retroorbital bleeding or cardiac puncture; it remains
possible that portal transferrin saturations are higher.
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| Fig 2.
Iron metabolism in Hfe mutant mice. (a) Liver iron
content was determined for 4-week-old 129/SvEvTac mice as previously
described10 and expressed as micrograms per gram wet weight ± standard error. Genotypes are abbreviated as follows: wild-type
(+/+), Hfe C282Y homozygous (Y/Y ), and
Hfe null homozygous ( /). All differences between
genotypes were statistically significant when P values were
determined by Welch correction of the unpaired t-test. (b)
Hepatic iron was visualized by Prussian blue staining of tissue
sections from wild-type and mutant F2 mice with a C57BL/6J × 129/SvEvTac background. Nonheme iron deposits appear blue. (c)
Spleen iron was determined for 4-week-old 129/SvEvTac mice using the
same method as was used for liver iron, and expressed as microgram per
gram wet weight ± standard error. Differences between wild-type mice
and each mutant strain were statistically significant according to
P values determined by Welch correction of the unpaired
t-test. The mutant strains were not significantly different
from each other.
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Mice homozygous for each Hfe mutation had less splenic nonheme
iron than wild-type mice, despite systemic iron overload (Fig 2c). This
may be because mouse spleen is an active site of erythropoiesis, and
most splenic storage iron is found in macrophages. This may be
analogous to human hemochromatosis, where patients have been shown to
have decreased iron in bone marrow macrophages.9
In conclusion, the C282Y mutation clearly predisposes to iron loading,
but is not as severe as a null allele. Heterozygosity for either mutant
Hfe allele results in increased iron stores, consistent with
the notion that the prevalence of the human mutation may result from
heterozygote advantage. Analogous to human patients, mice carrying
Hfe mutations also have depleted splenic iron stores, further
confirming that these mouse mutants offer a valid system for studying
the human disease. Finally, liver iron loading begins before
circulating transferrin is fully saturated, suggesting that it may
occur in the absence of significant levels of nontransferrin-bound iron. This has implications for the mechanism of hepatic iron loading,
and suggests that it may begin earlier than generally appreciated in
hemochromatosis patients.
| |
ACKNOWLEDGMENT |
We thank P. Leder for providing TC1 ES cells, R. Mortenson for the
targeting vector, Y. Fujiwara and S. Orkin for assistance with
blastocyst injections, and H. Westphal and F. Alt for providing mice
expressing Cre recombinase.
| |
FOOTNOTES |
Submitted March 5, 1999; accepted March 26, 1999.
J.E.L. is supported by National Institutes of Health (NIH) Grant No.
K08 HL03503; M.D.F. is supported by NIH Grant No. K08 HL03600 and a
fellowship from the American Liver Foundation. N.C.A. is an Associate
Investigator of the Howard Hughes Medical Institute.
Address reprint requests to Nancy C. Andrews, MD, PhD, Howard Hughes
Medical Institute, Enders 720, Children's Hospital, 300 Longwood Ave,
Boston, MA; e-mail: nandrews{at}rascal.med.harvard.edu.
| |
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J. D. Phillips, L. K. Jackson, M. Bunting, M. R. Franklin, K. R. Thomas, J. E. Levy, N. C. Andrews, and J. P. Kushner
A mouse model of familial porphyria cutanea tarda
PNAS,
December 22, 2000;
(2000)
11481398.
[Abstract]
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C. N. Roy and C. A. Enns
Iron homeostasis: new tales from the crypt
Blood,
December 15, 2000;
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4020 - 4027.
[Abstract]
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Z. J. Bulaj, R. S. Ajioka, J. D. Phillips, B. A. LaSalle, L. B. Jorde, L. M. Griffen, C. Q. Edwards, and J. P. Kushner
Disease-Related Conditions in Relatives of Patients with Hemochromatosis
N. Engl. J. Med.,
November 23, 2000;
343(21):
1529 - 1535.
[Abstract]
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C. C. Trenor III, D. R. Campagna, V. M. Sellers, N. C. Andrews, and M. D. Fleming
The molecular defect in hypotransferrinemic mice
Blood,
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96(3):
1113 - 1118.
[Abstract]
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G. Montosi, P. Paglia, C. Garuti, C. A. Guzman, J. M. Bastin, M. P. Colombo, and A. Pietrangelo
Wild-type HFE protein normalizes transferrin iron accumulation in macrophages from subjects with hereditary hemochromatosis
Blood,
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96(3):
1125 - 1129.
[Abstract]
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N. C. Andrews
Disorders of Iron Metabolism
N. Engl. J. Med.,
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341(26):
1986 - 1995.
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J. D. Phillips, L. K. Jackson, M. Bunting, M. R. Franklin, K. R. Thomas, J. E. Levy, N. C. Andrews, and J. P. Kushner
A mouse model of familial porphyria cutanea tarda
PNAS,
January 2, 2001;
98(1):
259 - 264.
[Abstract]
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R. E. Fleming, M. C. Migas, C. C. Holden, A. Waheed, R. S. Britton, S. Tomatsu, B. R. Bacon, and W. S. Sly
Transferrin receptor 2: Continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis
PNAS,
February 29, 2000;
97(5):
2214 - 2219.
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A. Waheed, J. H. Grubb, X. Y. Zhou, S. Tomatsu, R. E. Fleming, M. E. Costaldi, R. S. Britton, B. R. Bacon, and W. S. Sly
Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis
PNAS,
March 5, 2002;
99(5):
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[Abstract]
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T. J. Sproule, E. C. Jazwinska, R. S. Britton, B. R. Bacon, R. E. Fleming, W. S. Sly, and D. C. Roopenian
Naturally variant autosomal and sex-linked loci determine the severity of iron overload in beta 2-microglobulin-deficient mice
PNAS,
April 24, 2001;
98(9):
5170 - 5174.
[Abstract]
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G. Nicolas, M. Bennoun, I. Devaux, C. Beaumont, B. Grandchamp, A. Kahn, and S. Vaulont
From the Cover: Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice
PNAS,
July 17, 2001;
98(15):
8780 - 8785.
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L. Schwake, A. W. Henkel, H. D. Riedel, T. Schlenker, M. Both, A. Migala, B. Hadaschik, N. Henfling, and W. Stremmel
Regulation of transferrin-induced endocytosis by wild-type and C282Y-mutant HFE in transfected HeLa cells
Am J Physiol Cell Physiol,
May 1, 2002;
282(5):
C973 - C979.
[Abstract]
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ABSTRACT
INTRODUCTION