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Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2502-2505
HFE Mutations Analysis in 711 Hemochromatosis Probands: Evidence
for S65C Implication in Mild Form of Hemochromatosis
By
Catherine Mura,
Odile Raguenes, and
Claude Férec
From the Centre de Biogénétique, ETSBO, CHU, UBO, BP454,
Brest, France.
 |
ABSTRACT |
Hereditary hemochromatosis (HH) is a common autosomal recessive
genetic disorder of iron metabolism. The HFE candidate gene encoding an HLA class I-like protein involved in HH was identified in
1996. Two missense mutations have been described: C282Y, accounting for
80% to 90% of HH chromosomes, and H63D, which is associated with a
milder form of the disease representing 40% to 70% of non-C282Y HH
chromosomes. We report here on the analysis of C282Y, H63D, and the
193A T substitution leading to the S65C missense substitution in a large series of probands and controls. The results confirm that
the C282Y substitution was the main mutation involved in hemochromatosis, accounting for 85% of carrier chromosomes, whereas the H63D substitution represented 39% of the HH chromosomes that did
not carry the C282Y mutation. In addition, our screening showed that
the S65C substitution was significantly enriched in probands with at
least one chromosome without an assigned mutation. This substitution
accounted for 7.8% of HH chromosomes that were neither C282Y nor H63D.
This enrichment of S65C among HH chromosomes suggests that the S65C
substitution is associated with the mild form of hemochromatosis.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
HEREDITARY hemochromatosis (HH) is an
autosomal recessive disease affecting iron metabolism and is commonly
found in whites. Populations of northern European origin show the
highest frequency of HH, with 1 in 300 individuals
affected.1,2 HH is characterized by increased iron
absorption and progressive iron storage that results in organ damage.
The clinical consequences of iron overload can be prevented by early
diagnosis and treatment with repeated venesections. Because early
diagnosis during the asymptomatic phase would be more effective for
preventive treatment, a reliable genetic-based test is required. The
HFE gene was identified by positional cloning in
1996,3 and relevant studies have been performed that
support HFE as being the gene responsible for hemochromatosis. The HFE gene encodes an HLA class I-like protein that, in
association with  2-microglobulin, has an expression pattern
correlated with the localization of iron absorption.3-5 HFE
seems to play a role in iron uptake by interacting with the transferrin
receptor (TfR), leading to a decreased affinity of TfR for
transferrin.6-8
The single-base substitution 845GA (C282Y) has been well
characterized as being the main mutation responsible for
hemochromatosis in all the population studies performed throughout the
world. It accounts for 80% to 90% of HH chromosomes, with 81% to
90% of HH patients being homozygous for C282Y.3,9-14 The
functional relevance of the C282Y mutation has been clarified by cell
transfection assays showing that this mutation abolishes a conserved
cysteine that impairs 2-microglobulin association and cell surface
expression of the HFE protein.4,15 Hence, the C282Y
mutation eliminates the interaction with TfR that may be sufficient to
cause iron storage overload.7
Correlations between phenotype and genotype have also shown that
nonhomozygous probands for C282Y have lower iron overload than C282Y
homozygous subjects according to their iron status marker.10,12,13 It has been reported that, among non-C282Y HH chromosomes, 21% to 43%11-13,16 and possibly as many
as 64% to 73%, according to the last estimation from pooled
studies,14,17 bear the H63D (187CG) substitution,
indicating that the H63D frequency is increased among HH probands.
Compound heterozygotes C282Y/H63D account for approximately 7% of
hemochromatosis subjects, and the lower than expected frequency of H63D
homozygotes found among HH probands compared with the H63D frequency in
the population is evidence of the incomplete penetrance of the H63D
mutation. Thus, the H63D substitution may be considered as a genetic
variant that increases the risk of developing a mild form of
hemochromatosis.11-14,16,17 The functional significance of
H63D was recently shown in a cell transfection assay in which this
substitution led to a loss of ability to reduce the TfR affinity for
transferrin compared with wild-type HFE.7
Several studies, including the systematic sequencing of the coding
region performed on a total of 44 HH chromosomes that do not bear C282Y
or H63D in European and North American patients,11,13,18 have been performed on hemochromatosis subjects from different populations. Despite these reports, no other obvious mutation for HH,
except for a single delC mutation,19 have been described. Several polymorphisms have also been reported.18,20,21
These are predominantly localized in intron sequences except for one, namely 193AT, which leads to a serine-to-cysteine
substitution (S65C) localized in exon 2 in the vicinity of
H63D.21
In a previous study, we examined 478 probands for C282Y and H63D
mutations that accounted for 86.8% and 5.75% of HH chromosomes, respectively.13 Only 7.45% of HH chromosomes did not bear
either of these two mutations, and 10.8% of probands were incompletely characterized with at least one chromosome without an assigned mutation. C282Y and H63D substitutions accounted for a total of 92% of
HH alleles, suggesting that another mutation(s) is involved in HH. This
prompted us to examine the involvement of the S65C substitution in hemochromatosis.
| |
PATIENTS AND METHODS |
Probands and control subjects.
The study was performed on a series of 711 unrelated probands with
clinical hemochromatosis and 410 unrelated individuals randomly
selected as controls. The diagnosis of HH was based on the presence of
at least two of the following criteria: a transferrin saturation
greater than 60% in males and 50% in females, a serum ferritin
concentration greater than 400 µg/L in males and 300 µg/L in
females, or a serum iron concentration greater than 20 µmol/L. The
amount of iron removed by quantitative phlebotomy was estimated as
previously reported.13
Polymerase chain reactions (PCR) and restriction enzyme assay.
DNA was extracted from peripheral blood leukocytes. C282Y and H63D
substitutions were analyzed as previously described.13 The
193AT (S65C) substitution was detected with a HinfI
digest, the substitution abolishing a restriction site. First, exon 2 of the HFE gene was partly amplified using the primers and PCR conditions previously described for H63D analysis.13 Then,
10 µL of the PCR products was digested with 5 U of HinfI for
2 hours at 37°C and resolved on a 3% Nusieve 3:1 agarose gel (FMC
BioProducts, Rockland, ME). Amplification resulted in a
PCR product of 208 bp; the wild-type digest resulted in fragments of
147 bp and 61 bp.
Sequencing.
After specific amplification by PCR, the six coding exons and
exon-intron junctions of the HFE gene were all sequenced by dideoxynucleotide chain termination method using a Thermo Sequenase Terminator Cycle Sequencing kit (Amersham Pharmacia Biotech, Uppsala, Sweden).
Statistical analysis.
The Student's t-test was used to compare the mean value of
serum iron, serum ferritin, and transferrin saturation between groups
of probands. Fisher's exact test was used to compare the prevalence of
the S65C substitution among HH probands with controls.
| |
RESULTS |
Analysis of C282Y and H63D mutations.
The two substitutions known to be involved in hemochromatosis, namely
C282Y and H63D, were analyzed by PCR amplification of exons 4 and 2 of
the HFE gene followed by restriction digestion. Seven hundred
eleven unrelated probands and 410 control subjects from Brittany were
genotyped for C282Y and H63D (Table 1). We detected the C282Y mutation on 85% and 7.7% of patient and control chromosomes, respectively. The C282Y homozygous genotype accounted for
80% of probands and only 0.5% of controls. The H63D variant was
present in 5.8% of proband and 14% of control chromosomes and 8 patients (1.1%) and 3 controls (0.7%) were homozygous for this
variation, whereas 40 patients and 9 controls were compound heterozygotes C282Y/H63D. The H63D represented 39% of the HH
chromosomes that did not carry the C282Y mutation, showing a 2.6-fold
increase compared with controls (15%). Among the probands that were
neither homozygous nor compound heterozygous, the C282Y heterozygotes accounted for 33%, showing a 2.6-fold increase compared with controls. There was a clear correlation between proband genotype and iron overload. The nonhomozygous probands for C282Y had milder overload compared with the C282Y homozygotes, as shown by initial quantitative phlebotomy (<5 g of iron removed), serum iron, serum ferritin, and
transferrin saturation levels at diagnosis.
View this table:
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Table 1.
Genotype Frequencies Defined by C282Y and H63D Amino
Acid Substitutions in HFE and Mean Iron Status Markers ± Standard
Deviation
|
|
Analysis of the S65C substitution.
We developed a PCR restriction method to study the 193AT
substitution in the second exon of the HFE gene, which leads to serine 65-to-cysteine substitution. Sixteen S65C substitutions were
identified among the 410 control subjects and 10 were observed among
the 711 studied probands (Table 2). The S65C variant was never found in individuals with either the homozygous genotypes C282Y/C282Y and H63D/H63D or the compound heterozygotes C282Y/H63D, indicating that the S65C substitution and the other known mutations, C282Y and H63D, are mutually exclusive. Taking into account the control
chromosomes that were already known to carry C282Y or H63D (N = 178), a
total of 642 control chromosomes carried neither the C282Y substitution
nor the H63D, whereas 2.49% of them carried the S65C variant (16/642).
Ten probands carried the S65C allele and all of them carried at least
one chromosome with an unassigned mutation for HH. Thus, 10.7% (10/93)
of HH probands with incompletely characterized genotypes for HH carried
the S65C substitution; among them, compound heterozygotes accounted for
16% and 7.4% of C282Y and H63D carriers, respectively. The S65C
substitution represented 7.8% (10/128) of the HH chromosomes that were
neither C282Y nor H63D, whereas only 2.49% of control chromosomes
carried the S65C substitution. This represented a 3.1-fold enrichment compared with controls. Fisher's exact test was used to compare the
frequency of S65C among HH chromosomes with controls. A two-sided exact
test provided a P value of .0078. The S65C substitution was
thus significantly higher among the HH chromosomes not carrying the
C282Y or H63D subtitutions than in controls. We further analyzed the
HFE coding sequence of S65C carriers that did not show any additional variations. These 10 hemochromatic patients with the S65C
substitution had clinical and biochemical features typical of genetic
hemochromatosis (serum iron, 31.2 ± 2.3 µmol/L; serum ferritin,
646 ± 128 µg/L; transferrin saturation, 71% ± 21%).
The C282Y homozygotes and nonhomozygotes constitute two groups of
patients associated with severe and mild iron overload, respectively.
Analysis of the sex ratio between the two defined groups of HH probands
showed that the ratio of male-to-female HH probands was 4:1 (81% of
males), whereas among homozygous C282Y and nonhomozygous C282Y, it was
3:1 (72% of males) and 7:1 (90% of males), respectively. Thus, the
presence of a mutation with mild effect (H63D, S65C, or other unknown)
would increase the risk of developing this disease in males.
| |
DISCUSSION |
We have performed an investigation on a large series of HH probands and
controls by analyzing two known substitutions involved in HH as well as
another substitution, initially described as a polymorphism, occuring
in the coding sequence of HFE. Allele frequencies of C282Y,
H63D, and S65C were 7.7%, 14%, and 1.95% of control chromosomes,
respectively, and 85%, 5.8%, and 0.7% of HH chromosomes,
respectively. Moreover, a 2.6-fold increase of the H63D substitution
among non-C282Y HH chromosomes and a 2.6-fold increase of the S65C
substitution among non-C282Y, non-H63D HH chromosomes compared with
controls were significant.
This study confirms previous results concerning the prevalence of the
C282Y and H63D substitutions in HFE. Allele frequencies for C282Y and
H63D substitutions observed in a control population from Brittany were
similar to those reported from a British-Irish population, ie, 6.4%
for C282Y and 12.8% for H63D.22 Thus, our results agree
with a Celtic origin of the Brittany population. The 845GA
(C282Y) substitution is the most prevalent mutation involved in HH and
homozygosity representing 80% of HH probands is associated with the
most severe form of this disease, which correlates with the results
obtained in vitro showing that the mutation abolishes the HFE function
in iron uptake. The HH chromosomes that do not carry the C282Y mutation
show a higher frequency of the 187CG substitution (H63D;
39%) than controls, although only 1.1% of the probands were
homozygous. Thus, the H63D substitution is clearly associated with an
increased storage of iron, although this variant is associated with a
milder form of the disease and shows an incomplete penetrance. This is
relevant, because a H63D substitution, at least in vitro, leads only to
a reduced activity of HFE protein. In the present study homozygous
probands represented 81.1%, compound heterozygotes represented 5.6%,
and 62% of the remaining probands were heterozygotes for the C282Y or
H63D mutations.
The C282Y and H63D substitutions accounted for a total of 90.8% of HH
alleles in our study. The remaining chromosomes showed heterogeneity of
haplotypes defined by markers3,13; thus, we might expect to
find only rare mutations in the cases in which HH is linked to the
HFE gene in these individuals. We examined the prevalence of
the 193AT (S65C) substitution occuring in the coding sequence
of HFE in HH probands and controls. Interestingly, 7.2% of HH
chromosomes carrying neither the C282Y nor H63D mutations bore the S65C
substitution, compared with only 2.49% of control chromosomes. Despite
the low frequency of the S65C subtitution, a Fisher exact test showed a
statistically significant difference. Among the series of probands,
16% of C282Y heterozygotes and 7.4% of H63D heterozygotes also
carried the S65C substitution. Thus, the S65C could be another variant
contributing to iron overload in mildly affected hemochromatosis subjects.
Another interesting point is that the male-to-female sex-ratio was 3:1
among the homozygous HH probands for C282Y and 7:1 for the remaining
probands. Male individuals carrying two of these mild mutations or one
in combination with C282Y would be more at risk of developing
hemochromatosis than females. Indeed, due to menstruation and
pregnancy, females seem to be protected from developing iron
overload,23 which explains why male individuals carrying
mild mutations are more prevalent among HH probands than females. Thus,
the risk of developing the disease is associated with the HFE
genotype and the subject's sex.
The functional significance of S65C substitution in mild iron overload
should be examined. One can hypothesize that the S65C substitution
located in the proximity of H63D may not be able to reduce the affinity
of TfR for transferrin as efficiently as the wild-type, as demonstrated
for the H63D mutant protein.7 Another possible explanation
may be that the 193AT is a polymorphism linked to a different
genetic alteration affecting the level of HFE expression and
that S65C has no effect on its own.
In conclusion, our present data provide evidence that the S65C
substitution is significantly higher among HH chromosomes that are
noncarriers of the C282Y or H63D substitutions. These results bring
additional refinement to the correlation between phenotypic heterogeneity and genotype among HH probands. The main mutation associated with high iron overload, C282Y, accounted for 85% of HH
chromosomes, whereas the remaining chromosomes were composed mainly of
the two variants associated with milder iron overload, H63D and S65C,
accounted for 39% and 4.7%, respectively. Homozygotes for C282Y and
H63D represented 80% and 1.1%, respectively; the compound
heterozygotes consisted of 5.6% of C282Y/H63D and 1% of C282Y/S65C
and H63D/S65C.
| |
FOOTNOTES |
Submitted September 28, 1998; accepted December 8, 1998.
Supported by grants from CRI 9607 and Association de Transfusion
Sanguine et de Biogénétique Gaetan Saleun.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Catherine Mura, PhD, Centre de
Biogénétique, ETSBO, CHU, UBO, BP454, 46 rue Félix Le
Dantec, F-29275 Brest, France; e-mail: Catherine.Mura{at}univ-brest.fr.
| |
REFERENCES |
1.
Edwards CQ, Griffen LM, Goldgar D, Drummond C, Skolnick MH, Kushner JP:
Prevalence of hemochromatosis among 11065 presumably healthy blood donors.
N Engl J Med
318:1355, 1988[Abstract]
2.
Leggett BA, Halliday JW, Brown NN, Bryant S, Powell LW:
Prevalence of haemochromatosis among asymptomatic Australians.
Br J Haematol
74:525, 1990[Medline]
[Order article via Infotrieve]
3.
Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R, Ellis MC, Fullan A, Hinton LM, Jones NL, Kimmel BE, Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, McClelland E, Meyer NC, Mintier GA, Moeller N, Moore T, Morikang E, Prass CE, Quintana L, Starnes SM, Schatzman RC, Brunke KJ, Drayna DT, Rish NJ, Bacon BR, Wolff RK:
A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.
Nat Genet
13:399, 1996[Medline]
[Order article via Infotrieve]
4.
Feder JN, Tsuchihashi Z, Irrinki A, Lee VK, Mapa FA, Morikang E, Prass CE, Starnes SM, Wolff RK, Parkkila S, Sly WS, Schatzman RC:
The hemochromatosis founder mutation in HLA-H disrupts 2-microglobulin interaction and cell surface expression.
J Biol Chem
272:14025, 1997[Abstract/Free Full Text]
5.
Parkkila S, Waheed A, Britton RS, Feder JN, Tsuchihashi Z, Schatzman RC, Bacon BR, Sly WS:
Immunochemistry of HLA-H, the protein defective in patients with hereditary hemochromatosis, reveals unique pattern of expression in gastrointestinal tract.
Proc Natl Acad Sci USA
94:2534, 1997[Abstract/Free Full Text]
6.
Parkkila S, Waheed A, Britton RS, Bacon BR, Zhou XY, Tomatsu S, Fleming RE, Sly WS:
Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis.
Proc Natl Acad Sci USA
94:1319, 1997
7.
Feder JN, Penny DM, Irrinki A, Lee VK, Lebron JA, Watson N, Tsuchihashi Z, Sigal E, Bjorkman PJ, Schatzman RC:
The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding.
Proc Natl Acad Sci USA
95:1472, 1998[Abstract/Free Full Text]
8.
Zhou XY, Tomatsu S, Fleming RE, Parkkila S, Waheed A, Jiang J, Fei Y, Brunt EM, Ruddy DA, Prass CE, Schatzman RC, O'Neil R, Britton RS, Bacon BR, Sly WS:
HFE gene knockout produces mouse model of hereditary hemochomatosis.
Proc Natl Acad Sci USA
95:2492, 1998[Abstract/Free Full Text]
9.
Jazwinska EC, Cullen LM, Busfield F, Pyper WR, Webb SI, Powell LW, Morris CP, Walsh TP:
Haemochromatosis and HLA-H.
Nat Genet
14:249, 1996[Medline]
[Order article via Infotrieve]
10.
Jouanolle AM, Gandon G, Jézéquel P, Blayau M, Campion ML, Yaouanq J, Mosser J, Fergelot P, Chauvel B, Bouric P, Carn G, Andrieux N, Gicquel I, Le Gall JY, David V:
Haemochromatosis and HLA-H.
Nat Genet
14:251, 1996[Medline]
[Order article via Infotrieve]
11.
Carella M, D'Ambrosio L, Totaro A, Grifa A, Valentino MA, Piperno A, Girelli D, Roetto A, Franco B, Gasparini P, Camashella C:
Mutation analysis of the HLA-H gene in Italian hemochromatosis patients.
Am J Hum Genet
60:828, 1997[Medline]
[Order article via Infotrieve]
12.
Beutler E, Gelbart T, West C, Lee P, Adams M, Blackstone R, Pockros P, Kosty M, Venditti CP, Phatak PD, Seese NK, Chorney KA, Ten Elshof AE, Gerhard GS, Chorney M:
Mutation analysis in hereditary hemochromatosis.
Blood Cells Mol Dis
22:187, 1996[Medline]
[Order article via Infotrieve]
13.
Mura C, Nousbaum JB, Verger P, Moalic MT, Raguenes O, Mercier AY, Ferec C:
Phenotype-genotype correlation in haemochromatosis patients.
Hum Genet
101:271, 1997[Medline]
[Order article via Infotrieve]
14.
Risch N:
Haemochromatosis, HFE and genetic complexity.
Nat Genet
17:375, 1997[Medline]
[Order article via Infotrieve]
15.
Waheed A, Parkkila S, Zhou XY, Tomatsu S, Tsuchihashi Z, Feder JN, Schatzman RC, Britton RS, Bacon BR, Sly WS:
Hereditary hemochromatosis: Effects of C282Y and H63D mutations on association with 2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells.
Proc Natl Acad Sci USA
94:12384, 1997[Abstract/Free Full Text]
16.
Borot N, Roth MP, Malfroy L, Demangel C, Vinel JP, Pascal JP, Coppin H:
Mutations in the MHC class I-like candidate gene for hemochromatosis in French patients.
Immunogenetics
45:320, 1997[Medline]
[Order article via Infotrieve]
17.
Beutler E:
The significance of the 187G (H63D) mutation in hemochromatosis.
Am J Hum Genet
61:762, 1997[Medline]
[Order article via Infotrieve]
18.
Beutler E, West C, Gelbart T:
HLA-H and associated proteins in patients with hemochromatosis.
Mol Med
3:397, 1997[Medline]
[Order article via Infotrieve]
19.
Pointon JJ, Shearman JD, Merryweather-Clarke AT, Robson KJH:
A single nucleotide deletion in the putative haemochromatosis gene in a patient who is negative for both the C282Y and H63D mutations. International Symposium Iron in Biology and Medicine. Saint-Malo, France, 1997, p 268.
20.
Totaro A, Grifa A, Carella M, D'Ambrosio L, Valentino M, Roth MP, Borot N, Coppin H, Roetto A, Camaschella C, Gasparini P:
Hereditary hemochromatosis: A HpaI polymorphism within the HLA-H gene.
Mol Cell Probes
11:229, 1997[Medline]
[Order article via Infotrieve]
21.
Douabin V, Deugnier Y, Jouanolle AM, Moirand R, Macqueron G, Gireau A, Le Gall JY, David V:
Polymorphisms in the haemochromatosis gene. International Symposium Iron in Biology and Medicine. Saint-Malo, France, 1997, p 267.
22.
Merryweather-Clarke AT, Pointon JJ, Shearman JD:
Global prevalence of putative haemochromatosis mutations.
J Med Genet
34:275, 1997[Abstract/Free Full Text]
23.
Moirand R, Adams PC, Bicheler V, Brissot P, Deugnier Y:
Clinical features of genetic hemochromatosis in women compared with men.
Ann Intern Med
127:105, 1997[Abstract/Free Full Text]
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|
P Holmstrom, J Marmur, G Eggertsen, M Gafvels, and P Stal
Mild iron overload in patients carrying the HFE S65C gene mutation: a retrospective study in patients with suspected iron overload and healthy controls
Gut,
November 1, 2002;
51(5):
723 - 730.
[Abstract]
[Full Text]
[PDF]
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D Trinder, C Fox, G Vautier, and J K Olynyk
Molecular pathogenesis of iron overload
Gut,
August 1, 2002;
51(2):
290 - 295.
[Abstract]
[Full Text]
[PDF]
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C. Toomajian and M. Kreitman
Sequence Variation and Haplotype Structure at the Human HFE Locus
Genetics,
August 1, 2002;
161(4):
1609 - 1623.
[Abstract]
[Full Text]
[PDF]
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A. Mattman, D. Huntsman, G. Lockitch, S. Langlois, N. Buskard, D. Ralston, Y. Butterfield, P. Rodrigues, S. Jones, G. Porto, et al.
Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation
Blood,
July 18, 2002;
100(3):
1075 - 1077.
[Abstract]
[Full Text]
[PDF]
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E Ryan, V Byrnes, B Coughlan, A-M Flanagan, S Barrett, J C O'Keane, and J Crowe
Underdiagnosis of hereditary haemochromatosis: lack of presentation or penetration?
Gut,
July 1, 2002;
51(1):
108 - 112.
[Abstract]
[Full Text]
[PDF]
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TOP
ABSTRACT
INTRODUCTION
