Download A founder mutation of the potassium channel KCNQ1 in long

Journal of the American College of Cardiology
© 2001 by the American College of Cardiology
Published by Elsevier Science Inc.
Vol. 37, No. 2, 2001
ISSN 0735-1097/01/$20.00
PII S0735–1097(00)01124-4
A Founder Mutation of the Potassium
Channel KCNQ1 in Long QT Syndrome
Implications for Estimation of
Disease Prevalence and Molecular Diagnostics
Kirsi Piippo, MSC,* Heikki Swan, MD,* Michael Pasternack, PHD,† Hugh Chapman, PHD,†
Kristian Paavonen, MD,* Matti Viitasalo, MD,* Lauri Toivonen, MD,* Kimmo Kontula, MD
Helsinki, Finland
We took advantage of the genetic isolate of Finns to characterize a common long QT
syndrome (LQTS) mutation, and to estimate the prevalence of LQTS.
BACKGROUND The LQTS is caused by mutations in different ion channel genes, which vary in their
molecular nature from family to family.
METHODS
The potassium channel gene KCNQ1 was sequenced in two unrelated Finnish patients with
Jervell and Lange-Nielsen syndrome (JLNS), followed by genotyping of 114 LQTS probands
and their available family members. The functional properties of the mutation were studied
using a whole-cell patch-clamp technique.
RESULTS
We identified a novel missense mutation (G589D or KCNQ1-Fin) in the C-terminus of the
KCNQ1 subunit. The voltage threshold of activation for the KCNQ1-Fin channel was
markedly increased compared to the wild-type channel. This mutation was present in
homozygous form in two siblings with JLNS, and in heterozygous form in 34 of 114 probands
with Romano-Ward syndrome (RWS) and 282 family members. The mean (⫾ SD)
rate-corrected QT intervals of the heterozygous subjects (n ⫽ 316) and noncarriers (n ⫽ 423)
were 460 ⫾ 40 ms and 410 ⫾ 20 ms (p ⬍ 0.001), respectively.
CONCLUSIONS A single missense mutation of the KCNQ1 gene accounts for 30% of Finnish cases with
LQTS, and it may be associated with both the RWS and JLNS phenotypes of the syndrome.
The relative enrichment of this mutation most likely represents a founder gene effect. These
circumstances provide an excellent opportunity to examine how genetic and nongenetic
factors modify the LQTS phenotype. (J Am Coll Cardiol 2001;37:562– 8) © 2001 by the
American College of Cardiology
OBJECTIVES
The long QT syndrome (LQTS) is an inherited disorder of
cardiac repolarization, characterized by electrocardiographic
(ECG) abnormalities, syncopal attacks and risk of sudden
death due to ventricular tachyarrhythmias such as torsade de
pointes (1,2). The LQTS may occur as an autosomally
dominantly inherited form (Romano-Ward syndrome,
RWS) (3,4), or as a part of the autosomally recessively
inherited Jervell and Lange-Nielsen syndrome (JLNS) (5) in
which prolongation of the QT interval is associated with
sensorineural deafness. The exact prevalence of LQTS
remains to be determined, although an estimate of 1 in
10,000 has been suggested (6). The LQTS is associated
with significant morbidity and mortality, with estimated
annual rates of 5% and 1% for syncope and death, respectively (2).
Until now, mutations of five different genes, including
those encoding the cardiac potassium channel alphasubunits KCNQ1 (former KVLQT1) (7) and HERG (8),
From the *Department of Medicine, University of Helsinki, Helsinki, Finland, and
†Institute of Biotechnology, University of Helsinki, Helsinki, Finland. Preliminary
data were presented at the 71st Scientific Sessions of the American Heart Association,
Dallas, Texas, November 8 –11, 1998. This study was supported by grants from the
Finnish Academy, the Sigrid Juselius Foundation, the Instrumentarium Science
Foundation, the Finnish Foundation for Cardiovascular Research and the Research
and Science Foundation of Farmos.
Manuscript received May 23, 2000; revised manuscript received August 23, 2000,
accepted October 4, 2000.
beta-subunits minK (KCNE1) (9) and MiRP1 (KCNE2)
(10) as well as the sodium channel SCN5A (11) have been
found to underlie LQTS. The most prevalent form of
LQTS appears to be that caused by mutations of the
potassium channel KCNQ1 (LQT1), accounting for some
50% of the cases with RWS (7). Both KCNQ1 and minK
proteins assemble to form the slowly activating component
of the delayed rectifier potassium current (IKs) present in
heart and inner ear (12,13), and mutations of either of them
may be the underlying molecular pathology in the JLNS
when present in a homozygous form (14,15).
The molecular nature of the causative mutation typically
varies from family to family with LQTS. However, in
Finland a founder point mutation of the KCNQ1 gene,
located relatively close to the cytoplasmic tail of the ion
channel subunit, was identified in a large number of LQTS
probands.
METHODS
Characterization of patients and controls. Three children
(two brothers and a nonrelated boy) with prolonged corrected QT (QTc) interval and congenital deafness, compatible with the diagnosis of JLNS, were initially investigated
(Fig. 1). Clinical records, ECGs, and deoxyribonucleic acid
(DNA) samples from 114 apparently unrelated probands
JACC Vol. 37, No. 2, 2001
February 2001:562–8
Abbreviations and Acronyms
DNA ⫽ deoxyribonucleic acid
ECG ⫽ electrocardiogram/electrocardiographic
JLNS ⫽ Jervell and Lange-Nielsen syndrome
LCSD ⫽ left cardiac sympathetic denervation
LQTS ⫽ long QT syndrome
LQT1 ⫽ LQT1 type of long QT syndrome
PCR ⫽ polymerase chain reaction
QTc ⫽ QT interval corrected for heart rate with
Bazett’s formula (ms)
RWS ⫽ Romano-Ward syndrome
SIDS ⫽ sudden infant death syndrome
(80 females, 34 males; mean age (⫾ SD) 38 ⫾ 18, range 2
to 79 years) from families with RWS were subsequently
examined. Diagnostic criteria included prolonged rateadjusted QT (QTc) interval (⬎440 ms) and at least one
symptomatic episode (syncope or tachyarrhythmia) or a
family history of LQTS. The QTc interval was measured
from standard 12-lead ECG using lead II.
All index cases were of Finnish origin. The birthplaces of
the oldest obligate mutation carriers in each family were
Piippo et al.
KCNQ1-Fin Mutation and Long QT Syndrome
563
traced using local parish registers. The study was approved
by the Ethical Review Committee of the Department of
Medicine and was in accordance with the Helsinki Declaration. All subjects gave their informed consent. Control
DNA samples were obtained from 200 unrelated healthy
adult individuals (men and women equally).
Genetic analysis. All exons of the KCNQ1 gene were
amplified by polymerase chain reaction (PCR) with primers
published previously (7) or with novel primers designed
according to Lee et al. (16). A forward primer 5⬘GGATCCTAATGCCCAGGATGATC-3⬘ and reverse
primer 5⬘-GTCGACTTCATGGGGAAGGCTTC-3⬘
were used to amplify the whole coding sequence of the
minK gene. The resulting amplicons were sequenced using
ABI Prism 377 DNA sequencer (PE Biosystems, Foster
City, California). For specific detection of the G589D
mutation, primers 5⬘-GCAAAAGAGCAAGGATC
GCG-3⬘ and 5⬘-CTTGTCTTCTACTCGGTTCAG-3⬘
were used to amplify a 64-bp fragment of exon 14. After
PCR, the samples were digested with the enzyme HhaI
(New England Biolabs, Beverly, Massachusetts), followed
by electrophoresis on a 12% polyacrylamide gel. The normal
Figure 1. Pedigrees of families 1012 and 1034. Squares represent males, circles are females and symbols with slash mark represent deceased subjects.
Half-filled symbols indicate heterozygous KCNQ1-Fin carriers, filled symbols homozygous KCNQ1-Fin carriers and half-striped symbols are
heterozygous Y171X carriers. Open symbols denote unaffected individuals verified by deoxyribonucleic acid (DNA) assay. Subjects IV/6 and IV/8 in family
1012 and III/7 in family 1034 have Jervell and Lange-Nielsen syndrome (JLNS). The QTc interval (ms) is shown under each symbol; those marked with
an asterisk have been recorded during medication.
564
Piippo et al.
KCNQ1-Fin Mutation and Long QT Syndrome
allele is cleaved into two fragments (38 and 26 bp in size),
whereas the allele corresponding to the G589D mutation
remains uncleaved (64 bp).
Three highly polymorphic microsatellite markers
(D11S860, D11S1318 and TH) were studied to construct
possible disease-associated haplotypes. Genetic distances
and order of markers were determined by combining the
data in a genetic map and in a physical map (17) of the
corresponding area.
In vitro mutagenesis and electrophysiological studies.
Complementary DNAs (cDNAs) for KCNQ1 (AF000571)
and minK (L33815) in the pIRES-CD8 vector were used in
these studies. The G589D mutation was introduced into
the KCNQ1 cDNA using the QuickChange site-directed
mutagenesis kit according to the manufacturer’s instructions
(Stratagene, La Jolla, California). Transfections for transient in vitro expression studies in COS cells were made
using the diethylaminoethyl-dextran precipitate method.
Whole-cell membrane currents were measured and analyzed
using a Biologic RK 400x patch-clamp amplifier and
pCLAMP software (Axon Instruments, Foster City, California) essentially as described previously (18).
Statistical analysis. The mean QTc intervals in different
groups were compared to each other using the Student t
test. For comparison of dichotomous variables a standard
chi-square test was used. A p value ⬍0.05 was considered
statistically significant.
RESULTS
Identification of a common cause for LQTS in Finland.
The entire coding regions of the minK and KCNQ1 genes
were screened for mutations in two unrelated JLNS probands (Fig. 1). Survey of the minK gene disclosed no
mutations. When the KCNQ1 gene was sequenced, two
different mutations were identified: a change from G to A at
nucleotide 1876 of exon 14, predicted to result in a
substitution of aspartic acid for glycine at position 589
(G589D), and a C to G substitution at nucleotide 623 in
exon 2, resulting in a premature stop codon at position 171
(Y171X) and predicted synthesis of a truncated protein. The
G589D mutation is located in the cytoplasmic carboxyterminal portion of the ion channel subunit, whereas the
Y171X truncation takes place right after the second transmembrane domain S2. The two brothers with JLNS (family
1012) were homozygous for the G589D substitution,
whereas the JLNS patient of family 1034 was a compound
heterozygote, carrying both the G589D and Y171X mutation.
Using mutation-specific PCR assays, the occurrence of
the G589D and Y171X mutations was screened in members
of the index families (Fig. 1) and in 110 additional unrelated
Finnish probands with RWS. In the index families, 24
subjects heterozygous for the G589D and four heterozygous
for the Y171X mutation were identified. The Y171X
heterozygotes had normal to marginally prolonged QTc
JACC Vol. 37, No. 2, 2001
February 2001:562–8
intervals and no reported symptoms. A total of 34 of the 114
(30%) unrelated RWS probands were heterozygous for the
G589D mutation, whereas there was no additional case that
was positive for the Y171X mutation. Until now, 705 family
members of the 34 G589D positive probands have been
screened for the presence of this mutation, with identification of 316 heterozygotes altogether. Investigation of DNA
samples from 200 unrelated healthy Finns did not reveal any
individual positive for either the G589D or Y171X mutation. Because of its relatively common occurrence, the
G589D substitution was designated as the KCNQ1-Fin
mutation.
Functional expression of KCNQ1-Fin. When coexpressed with minK, the KCNQ1-Fin construct produced
functional channels in COS cells, but the currents were
much smaller than those observed for the normal (KCNQ1wt) cDNA, and there was a pronounced rightward shift in
the voltage of activation, with mean (⫾ SE) half-activation
voltages of 11.0 ⫾ 2.2 mV and 41.3 ⫾ 2.9 mV for
KCNQ1-wt and KCNQ1-Fin, respectively (Fig. 2). Moreover, detectable KCNQ1-Fin currents were present in only
4 of 23 cells expressing the CD8 reporter, whereas all 21
CD8-positive cells transfected with KCNQ1-wt, or, simultaneously, with KCNQ1-wt and KCNQ1-Fin in a 1:1 ratio,
displayed robust currents. No significant differences were
seen in the mean current amplitudes, activation voltages or
activation time constants between cells expressing
KCNQ1-wt alone or KCNQ1-wt together with KCNQ1Fin (data not shown), suggesting that KCNQ1-Fin does
not contribute substantially to the currents recorded when
the KCNQ1-wt and KCNQ1-Fin constructs are coexpressed. The mean (⫾ SE) deactivation time constants
observed at ⫺40 mV were similar for KCNQ1-wt (993 ⫾
56 ms, n ⫽ 7) and KCNQ1-Fin (965 ⫾ 54 ms, n ⫽ 4).
Clinical findings in homozygous and heterozygous individuals. The QTc values of the two KCNQ1-Fin homozygotes were 661 ms and 592 ms (Fig. 1). The older of them
had a syncopal spell while swimming, despite ongoing
beta-antiadrenergic medication. After subsequent left cardiac sympathetic denervation (LCSD) he has remained
symptom-free for 10 years. Although the younger brother
was treated with beta-antiadrenergic medication from birth
on, he died at the age of nine in his first cardiac event. The
heterozygous parents of the siblings had prolonged QTc
intervals (522 ms and 517 ms) but were asymptomatic. The
QTc value of the compound heterozygote, carrying both the
KCNQ1-Fin and Y171X mutation, was 566 ms (Fig. 1).
He was likewise treated with beta-antiadrenergic medication from birth on and subsequently with a cardiac pacemaker, yet he experienced a syncopal spell while swimming
at the age of two years. The LCSD was performed at the
age of 10 years, whereafter he has remained symptom-free
(follow-up 2.5 years). All three children were deaf since
birth.
The mean QTc interval of the heterozygous KCNQ1Fin carriers was significantly longer than that of the non-
Piippo et al.
KCNQ1-Fin Mutation and Long QT Syndrome
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February 2001:562–8
565
Figure 2. In vitro expression of the KCNQ1-Fin mutation in COS cells. (a) Whole-cell patch-clamp recordings from cells transfected with KCNQ1-wt ⫹
minK; (b) KCNQ1-wt ⫹ KCNQ1-Fin ⫹ minK; and (c) KCNQ1-Fin ⫹ minK. The relative activation curves obtained from the immediate tail are plotted
in (d). The common voltage protocol used in these experiments is shown in (e).
carriers (Table 1). The mean (⫾ SD) QTc of the 34
heterozygous index cases (490 ⫾ 40 ms) was longer than the
mean (⫾ SD) QTc of the remaining family members
positive for KCNQ1-Fin (450 ⫾ 30, p ⬍ 0.001). Using the
same QTc interval length 440 ms applied to choose proTable 1. Clinical Characteristics of Heterozygous Carriers and
Noncarriers of the KCNQ1-Fin (G589D) Mutation in
34 Families*
Variable
Males/Females (n)
Age (yrs)
Range of ages (yrs)
QTc (ms)
Range of QTc (ms)
Number (%) of symptomatic
individuals
Triggers of symptoms‡
Swimming
Other physical effort
Anxiety
Medication§
Sleep
Undefined㛳
Carriers
(n ⴝ 316)
Noncarriers
(n ⴝ 423)
142/174
37 ⫾ 21
2–87
460 ⫾ 40
390–580
83 (26%)
201/222
37 ⫾ 12
1–91
410 ⫾ 20†
350–490
ND
bands, a diagnostic specificity of 86% and sensitivity of 68%
were obtained. Among the KCNQ1-Fin heterozygotes,
women had on average a longer QTc (470 ⫾ 32 ms) than
did men (446 ⫾ 38 ms, p ⬍ 0.001) (Fig. 3). There were
altogether 83 (26%) symptomatic heterozygous carriers
comprising 52 females and 31 males. The percentage of the
symptomatic of all heterozygous individuals was not significantly different between adults (⬎16 years; 28%) and
children (ⱕ16 years; 19%). The mean (⫾ SD) QTc interval
17 (20%)
15 (18%)
16 (19%)
7 (8%)
4 (5%)
38 (46%)
*Figures indicate the mean ⫾ SD; †p ⬍ 0.001 between carriers and noncarriers;
‡Different causes may have triggered symptoms in the same individual; §Two patients
received terfenadine alone; in addition, terfenadine was used concomitantly with
chinin hydrochloride in one case and with ketoconazol in another. One patient used
thioridazine and another a combination of haloperidol and chlorprotixen hydrochloride. In addition, hydrochlortiazide was used in combination with celiprolol and
lisinopril in one patient; 㛳During normal daily activities.
QTc ⫽ QT interval corrected for heart rate according to Bazett’s formula; ND ⫽
not determined.
Figure 3. Number of established male (hatched bars) and female (open
bars) KCNQ1-Fin carriers according to their QTc interval classes, and
percentage of symptomatic individuals in the same classes (males and
females combined). None of the individuals included in this analysis had
any medication at the moment of QTc measurement. QTc ⫽ QT interval
corrected for heart rate according to Bazett’s formula.
566
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KCNQ1-Fin Mutation and Long QT Syndrome
JACC Vol. 37, No. 2, 2001
February 2001:562–8
of symptomatic mutation carriers (470 ⫾ 30 ms) was
significantly longer than that of the asymptomatic ones
(450 ⫾ 30 ms, p ⬍ 0.001), and there was an increasing
likelihood of occurrence of symptoms by increasing QTc
value (Fig. 3). In 48 cases (58%) the triggering factor for
syncope could unequivocally be related to physical or psychological stress, whereas seven patients (8%) had had a
cardiac event during various types of medication (Table 1).
A case of proposed sudden infant death syndrome.
Detailed questionnaires to the families identified a baby girl
who died at the age of three months while sleeping. As the
autopsy did not disclose any abnormalities and no family
data suggesting LQTS were available then, the case was
originally classified to represent a sudden infant death
syndrome (SIDS) of unknown origin. During the present
survey, one of the index carriers of the KCNQ1-Fin
mutation proved to be a second cousin of the proposed
SIDS case. The DNA extracted from paraffin-embedded
tissue samples of the deceased baby demonstrated heterozygosity for the KCNQ1-Fin mutation.
Existence of a founder gene. The occurrence of KCNQ1Fin in one-third of LQTS patients suggested a founder
gene effect. A common haplotype of 1500 kb between
markers D11S860 and D11S1318 could indeed be detected
in 25 of 26 individuals in which analysis was feasible. When
family data were traced back to the level of the oldest
mutation carrier in each family, the birthplaces of the
affected ancestors were found to cluster in a belt-like fashion
from the eastern North Karelia (city of Joensuu) area to the
northwestern region of the city of Oulu (Fig. 4).
DISCUSSION
The present study demonstrates that a specific and potentially lethal gene mutation underlying severe arrhythmic
propensity can show relative enrichment at the population
level. Although presence of mutational hot spots of the
genes encoding cardiac potassium (19) and sodium (11,20)
channels has been suggested, there are no previous reports
on the incidence of arrhythmia founder genes widely in a
specific population. The common occurrence of the
KCNQ1-Fin mutation in the Finnish LQTS probands may
be attributed to the relatively benign nature of the mutation
itself as well as the population history of the Finns.
KCNQ1-Fin mutation is located in a conserved region
possibly responsible for subunit assembly. The KCNQ1Fin mutation affects the codon 589, located in the cytoplasmic tail downstream of the transmembrane domains of the
protein. There are previous reports on identification of
C-terminal mutations of the KCNQ1 subunit (14,21–25),
but the G589D mutation appears to represent the most
distal one of those whose electrophysiological characteristics
have been documented. The glycine 589 is conserved in the
KCNQ1 genes of Mus musculus (U70068), Rattus norwegicus (AJ133685) and Squalus acanthias (AJ223714), suggest-
Figure 4. Geographical distribution of ancestral KCNQ1-Fin carriers.
Each spot on the map represents the earliest recognized KCNQ1-Fin
carrier of the affected family (n ⫽ 34). The early immigration probably took
place from the east and the late immigration from the south and west. A
major internal movement started in the sixteenth century from southeastern Finland toward the western and northern parts of the country.
ing that the C-terminus may represent a unique regulatory
region for the KCNQ1 channels (22).
Recently, Schmitt et al. (26) described a domain between
residues 589 and 620 that may be critically important for
subunit assembly; they proposed that JLNS mutations are
characterized by their defective ability to subunit interaction. Our functional studies with KCNQ1-Fin support this
assumption. When expressed in vitro, the KCNQ1-Fin
construct was able to form functional channels to some
extent as a homomer. However, the expression efficiency of
KCNQ1-Fin in COS cells was subnormal as less than 20%
of the transfected cells displayed detectable KCNQ1-Finmediated currents. In agreement with low functional expression efficiency, no dominant negative effect was observed with KCNQ1-Fin in vitro. These data suggest that
the KCNQ1-Fin allele is unable to produce functional
tetramers efficiently because of a dysfunctional assembly
domain (26).
JACC Vol. 37, No. 2, 2001
February 2001:562–8
The mild phenotype of the heterozygotes may have
enabled enrichment of the KCNQ1-Fin mutation. Our
data confirm that the same KCNQ1 mutation can cause
JLNS in homozygous and RWS in heterozygous form.
Approximately one-fourth of the individuals heterozygous
for the KCNQ1-Fin mutation were symptomatic (Table 1),
a proportion somewhat lower than that proposed earlier
(27,28). There is also previous evidence that LQT1 (LQT1
type of long QT syndrome) patients with the C-terminal
mutations have milder phenotypes than do those with
mutations of the transmembrane domains of the same
channel (24,25,29). The occurrence of symptoms increased
with increasing QTc value: among all subjects with QTc
⬍440 ms, only 16% were symptomatic, whereas 50% were
symptomatic in the group of QTc ⬎500 ms (Fig. 3).
However, these data also demonstrate that mutation carriers
are at risk of cardiac events even when the QTc interval is
normal. In accordance with earlier findings among LQT1
patients (30,31), swimming appeared to be an important
risk factor for KCNQ1-Fin carriers, triggering symptoms in
20% of all instances.
In addition to its relatively benign nature, the population
history of the Finns may provide another prerequisite for the
prevalence of the KCNQ1-Fin mutation. The Finnish
population represents a genetic isolate due to effective
geographical and linguistic separation within the historical
period (32). The geographical distribution of the birthplaces
for the oldest KCNQ1-Fin carriers closely matches the
internal migration wave commenced from the southeast in
the sixteenth century (Fig. 4). The founder gene phenomenon is further supported by the common haplotype associated with the disease in virtually all affected individuals
examined. The affected haplotype common to all but one of
the probands was relatively short, comprising only 1500 kb.
Along with the distribution of ancestral birthplaces, this
suggests that the KCNQ1-Fin mutation was introduced
into the population some 500 to 750 years or 25 to 35
generations ago (33). Previously, a founder KCNQ1 mutation has been suggested to occur in five South African
families based on identical haplotype around the disease
locus (34).
Prevalence of LQTS in Finland. Very recently, we identified several Finnish LQTS families with a specific HERG
channel mutation (L552S), and we provided genetic and
genealogical evidence for its role as a founder gene (18).
Today, a combination of two simple PCR tests, one for the
KCNQ1-Fin and another for the HERG L552S mutation,
correctly identifies 35% of Finnish LQTS patients and is
used as an adjunct to clinical diagnostics. Until now,
LQTS-causing mutations have been detected in half (56/
114) of the Finnish index families with altogether 472
molecularly defined carriers ((18,27,35), unpublished observations, 2000), suggesting a minimum prevalence of 1:5000
for LQTS in the Finnish population of five million people.
We are not aware of any reports suggesting a higher
prevalence of LQTS in other populations.
Piippo et al.
KCNQ1-Fin Mutation and Long QT Syndrome
567
Conclusions and clinical implications. We have demonstrated that LQTS founder genes may occur in the population. It remains to be examined whether the KCNQ1-Fin
mutation occurs in other populations as well. The LQTS
founder genes should provide a useful model for studies in
which genetic or nongenetic factors, such as common gene
polymorphisms, life style factors, endocrine and metabolic
determinants as well as pharmaceutical substances, modify
the course and prognosis of the arrhythmic tendency.
Acknowledgments
We thank Dr. Jacques Barhanin for providing the KCNQ1
and minK cDNAs and for helpful discussions. Ms. Susanna
Tverin, Ms. Tuula Soppela-Loponen, Ms. Hanna Ranne
and Ms. Mari Palviainen are thanked for excellent technical
assistance.
Reprint requests and correspondence: Professor Kimmo Kontula, University of Helsinki, Department of Medicine, Haartmaninkatu 4, FIN-00290 Helsinki, Finland. E-mail: kimmo.
[email protected].
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