(Circulation. 1999;100:1077-1084.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Splicing Mutations in KCNQ1
A Mutation Hot Spot at Codon 344 That Produces In Frame Transcripts
From the Medical Genetics Unit, St George's Hospital Medical
School, London, England (A.M., C.F., Y.B.D., N.C., P.S., A.R.A., M.A.P.,
S.J.); INSERM U523 and IFR C
ur Muscle Vaisseaux, Hôpital
Pitié-Salpêtrière, Institut de Myologie, Paris, France
(C.D., N.N., P.G.); Paediatric Department, Macclesfield District General
Hospital, Macclesfield, England (I.S.); Service de Biochimie B and IFR
Cur Muscle Vaisseaux, Hôpital
Pitié-Salpêtrière, Paris (P.R.); Service de Cardiologie,
Hôpital Louis Pradel, Lyon (P.C.); and Service de Cardiologie,
Hôpital Lariboisière, Paris (I.D.), France.
Correspondence to S. Jeffery, Medical Genetics Unit, St George's Medical School, Cranmer Terrace, Tooting London, SW17 ORE, England.
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Abstract |
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Background—Long-QT syndrome is a monogenic disorder that produces cardiac arrhythmias and can lead to sudden death. At least 5 loci and 4 known genes exist in which mutations have been shown to be responsible for the disease. The potassium channel gene KCNQ1, previously named KVLQT1, on chromosome 11p15.5 is one of these.
Methods and Results—We initially analyzed one family
using microsatellite markers and found linkage to KCNQ1.
Mutation detection showed a G to C change in the last base of exon 6
(1032 G
C) that does not alter the coded alanine. Restriction digest
analysis in the family showed that only affected individuals
carried the mutation. A previous report suggested that a G to A
substitution at the same position may act as a splice mutation in
KCNQ1, but no data was given to support this hypothesis nor
was the transcription product identified. We have shown by
reverse-transcription polymerase chain reaction that 2 smaller bands
were produced for the KCNQ1 gene transcripts in addition to
the normal-sized transcripts when lymphocytes of affected individuals
were analyzed. Sequencing these transcripts showed a loss of
exon 7 in one and exons 6 and 7 in the other, but an in-frame
transcript was left in each instance. We examined other families in
whom long-QT syndrome was diagnosed and found another unreported
splice-site mutation, 922-1 GC, in the acceptor site of intron 5,
and 2 of the previously reported 1032 GA mutations. All these showed
a loss of exons 6 and 7 in the mutant transcripts, validating the
proposal that a consensus sequence is affected in the exonic mutations
and that the integrity of the base at position 1032 is essential for
correct processing of the transcript.
Conclusions—The 6 cases already reported in the literature with
the 1032 GA transition, the novel 1032 GC transversion, and a
recent GT transversion at the same base show that codon 344 is the
second most frequently mutated after codon 341, suggesting at least two
hotspots for mutations in
KCNQ1.
Key Words: long-QT syndrome • mutation • ion channels
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Long-QT syndrome (LQTS) is an inherited form of cardiac arrhythmia that can lead to sudden death.1 2 A recent report on 33 000 newborns suggested an increased risk for those shown to have prolonged QTc on day 3 or 4 of life.3 Inheritance is commonly autosomal-dominant, where the condition is known as Romano-Ward Syndrome (RWS),1 2 but there is also a rare recessive form, Jervell-Lange-Nielsen syndrome,4 with associated deafness. The genetic pattern is not simple, however, as incomplete penetrance occurs in the dominant mode,5 and a recent report has shown a family with RWS but recessive inheritance.6 Four genes are known to cause LQTS, all of which encode ion channels or associated proteins. At loci LQT1, LQT2, LQT3, and LQT5 are the genes KCNQ1,7 HERG,8 SCN5A,9 and KCNE1,10 11 respectively. The first 2 code for potassium-channel proteins, the third for a sodium channel, and the last for a protein that interacts with potassium channels.12 13 14 15 LQT4 is a genetic locus16 for which linkage has been shown for only 1 family. About 40 mutations have been described for KCNQ1, but the phenotypic effect of these changes must be dependent on environmental or other genetic factors to explain the high degree of non-penetrance. Mutations in both KCNE1 and KCNQ1 produce Jervell-Lange-Nielsen syndrome and RWS,10 11 17 18 19 20 21 and in one case, amino acid changes in the latter gene showed RWS clinical features with a recessive inheritance.6 The designation of an inheritance pattern may, in some cases, depend on whether the stimulus that provokes the symptoms is strong enough to show an effect in the heterozygous or homozygous state. Some mutations are likely to prove of greater pathological importance than others, and the degree of non-penetrance and the number of asymptomatic individuals in families with different mutations will provide evidence in this respect. In this study, we report on 3 splice mutations involving exons 6 and 7.
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Methods |
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Microsatellite Analysis
Microsatellites were examined using either silver staining on native or denaturing polyacrylamide gels or incorporation of 32P-
deoxycitidene triphosphate
(32P-CTP) on denaturing sequencing gels. Polymerase
chain reaction (PCR) for the nonradioactive gels was performed in a
total volume of 15 µL of a solution containing 60 µg of genomic
DNA, 1.5 mmol/L MgCl2, 0.2 mmol/L dNTP, 10 pmol/L
primers, and 1 U of Taq polymerase (Red Hot) and buffer supplied by the
manufacturer (Advanced Biotechnology). Amplification conditions
were an initial denaturation at 94°C for 3 minutes followed by 27
cycles at 94°C for 30 s, 55°C for 75 s, 72°C for
15 s, and a 6-minute extension at 72°C. A total of 3 µL of PCR
product was run on either 8% to 10% polyacrylamide gels
for 3 hours or 6% to 8% denaturing polyacrylamide gels for 50
to 90 minutes, depending on size.
Linkage Analysis
Linkage analysis was done using the M-LINK program of
the LINKAGE software, version 5.03.22 Penetrance
was assumed to be 0.80. Multipoint analysis was performed by
comparing the lodscores obtained when the long-QT locus was positioned
between markers D11S1318 and D11S1323 with that when it was placed
outside these flanking microsatellites.
PCR and SSCP
PCR for single-strand conformational polymorphism (SSCP)
analysis was carried out in a total volume of 25 µL of
solution using the same concentrations as above. Primers and primer
conditions were as detailed previously.23 SSCP was
performed using 3 µL of PCR product in 8 µL of formamide
buffer. After denaturing for 4 minutes, the result was loaded onto a
0.8x MDE (mutation detection enhancement) gel (National
Diagnostics), run overnight, and then visualized using
silver stain.
Sequencing
DNAs giving normal and abnormal SSCP patterns were reamplified
by PCR in 50 µL of solution. The result was then cleaned using
a Qiagen PCR purification column, and eluted with 30 µL of elution
buffer (10 mmol/L Tris, pH 8.5); 5 µL of it was then mixed with
4 µL dRhodamine Terminator Cycle Sequencing Ready Reaction (ABI) and
1 µL of primer (10 pmol/L). The mixture was then cycled as per
instructions, purified again through a Qiagen column, and
analyzed on the ABI 377 automated sequencer.
After reverse-transcription (RT) PCR, the PCR products were run out in low-melting-point agarose, and the bands were cut out and extracted using a freeze-squeeze method. An equal volume of 1x Tris/borate/EDTA (TBE) was added to the agarose, which was then melted, frozen on dry ice for 5 minutes, and then spun through a Spin-X column (Costar). After the DNA was precipitated, it was reamplified and sequenced as above.
Restriction Site Determination and Restriction Fragment Length
Polymorphism Analysis
Sequences were investigated for restriction endonuclease sites
using "map" (GCG program, Human Genome Mapping Project).
The G to C and the G to A mutations abolish an Aci site and,
therefore, all individuals were genotyped by PCR followed by
enzyme digestion with Aci. A total of 5 µL of the PCR
products that were used for SSCP were digested overnight at 37°C
with 5 U of enzyme in a total volume of 10 µL. This was then run on a
2% agarose gel.
RT-PCR
For family 10738, RNA was isolated from 300 µL of fresh blood
using the Purescript RNA Isolation Kit from Gentra Systems Inc. Blood
for RNA should be as fresh as possible, but it can be kept at 4°C for
up to 24 hours (A. Murray, BSc, unpublished data, 1999). The RNA
obtained was then resuspended in 20 µL of TBE; 5 µL of this
was used in the BRL Superscript Preamplication System, and 5 µL of
the resulting cDNA was used with the nested primer pairs 1L-18R and
5L-16R (shown below). Touch-down amplification conditions were from
70°C to 60°C as above. For the other families, total RNA was
obtained from lymphoblastoid cell lines (RNA Plus, Bioprobe Systems),
and cDNA was prepared using the First-Strand cDNA synthesis kit from
Pharmacia. Band sizes were estimated on agarose gels.
The primers (5' to 3') for RT-PCR were as follows: 1L, GAG ATC GTG CTG GTG GTG TTC T; 18R, GTC TCC CCT TCC AGG TCC; 5L, GGG CAT CCG CTT CCT GCA GA; and 16R, TCC AGC CGC CGC TCT TCT.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Clinical Details
In family 10738 (Figure 1
), the
proband came to our attention because of episodes of fainting between 4
and 6 years of age, often associated with swimming. The initial
diagnosis was possible epilepsy, but when his sister, who is 3 years
younger, began to have similar problems, the proband was seen as a
pediatric outpatient. He was found to have a QTc of 440 ms, which
increased to 526 ms after exercise. Re-examination of previous ECGs
that had been passed as normal showed similar, but less pronounced,
abnormalities. His sister had a resting QTc of 480 ms, which rose to
550 ms after exercise. Both children are now on ß-blockers and have
had no further symptoms. Examination of other family members revealed 3
with ECG abnormalities. The mother of the proband had a QTc of 470 ms,
the maternal uncle of the proband had a QTc of 446 ms and was presumed
by the cardiologists to be affected, and the grandmother had a QTc of
500 ms. No family members other than the proband and his sister had any
clinical symptoms.
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For family 10683 (Figure 1
), the proband was an 18-year-old boy who
died suddenly while swimming. The father had a QTc of 450 ms but was
asymptomatic. The sister of the proband experienced several
syncopes with seizures triggered by stress during childhood, which
ceased spontaneously during adolescence. At the death of her brother,
she was found to have a QTc of 522 ms. Her 3 children had prolonged
QTcs of 470, 472, and 451 ms. Only the first child had symptoms
(stress-induced syncope at 3 years of age), but all are on atenolol
because of the family history.
In family 2915 (Figure 1), no history of sudden death existed, and both
parents had normal QTcs. The proband experienced a syncopal event at 6
years of age, and resuscitation was necessary; an ECG showed a QTc of
452 ms. The child was given nadolol and has remained
asymptomatic.
Family 9350 (Figure 1) also has no history of sudden death. The proband
had a syncope while about to dive during swimming lessons and had other
events until the age of 12 years induced by stress. At that time, he
was diagnosed with a QTc of 475 ms. His father had a QTc of 462 ms but
is asymptomatic.
Molecular Genetics
Microsatellite markers were analyzed in family 10738, who
originated from England. The haplotype of the LQT1 markers
cosegregating with the disease is shown in Figure 1.24 The
two point lodscores for D11S1318 and D11S1323 were 0.83 and 1.3, with
both maximum at 
=0. Analysis comparing the likelihood of the
locus lying between these markers as opposed to outside them gave a
lodscore of 2.09. The other known loci for LQTS,
HERG,25 KCNE1,26
SCN5A,23 and LQT4,16
all gave negative lodscores in this family with the closest known
microsatellites (data not shown). The linkage data clearly suggested
that the mutated gene in this family was KCNQ1, and mutation
analysis on all exons was carried out using SSCP. The only band
shift was in exon 6 (Figure 2), and all
individuals classed as affected showed this mobility change. Sequencing
of this exon showed a GC change at position 1032 (Figure 2). The
amino acid coded at this position is alanine, and this silent
nucleotide change was in the third base of the codon. The
mutation abolishes an Aci site, and digestion with this
enzyme confirmed that all individuals with the SSCP band-shift carried
the mutation (data not shown).
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Abnormal SSCP patterns of exon 6 PCR products were also observed in
the probands of 3 French families (9350, 10683, and 2915). By direct
sequencing, a G to C transversion at position 922 minus 1 in the
splice-acceptor site of intron 5 was identified in the proband of
family 9350 (Figure 3). This novel
mutation was inherited from his father.
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In families 10683 and 2915, a G to A transition was found at position 1032. This transition of the last base of codon 344 has already been described in 5 families.27 28 As in family 10738 above, it should not affect the encoded alanine; however, because it is the last base of the exon, it has been suggested to cause abnormal splicing, although this has not been demonstrated.27 28
To test the hypothesis that these base changes at position 1032 did
indeed affect splicing, we took fresh blood samples from the proband in
family 10738 (III-2) and his mother (II-6) and performed RT-PCR. The
PCR was nested (Figure 4) to improve the
signal. As shown in Figure 4, a major band was produced from 3
unrelated normal individuals for both first and second rounds of PCR,
but in both affected individuals, 2 smaller bands of equal intensity
also existed. Band sizes are given in the legend to Figure 4. DNA from
all bands produced by RT-PCR was cut out and sequenced. In control
lymphocytes and normal cardiac tissue, the major band is the normal
transcript and the minor band is a transcript lacking exon 7. In
affected patients, the smallest band showed an absence of exons 6 and
7, whereas the larger one was missing exon 7 (Figure 4). Examination of
the transcripts induced by the 2 other mutations in lymphoblastoid cell
lines (1032 GA and 922-1C) from affected patients showed an absence
of both exons 6 and 7 only (data not shown).
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In family 2915, the mutation 1032 GA was not present in either
parent. Paternity was confirmed by the analysis of 5
microsatellites in the 3 family members, suggesting that it was a de
novo mutation that occurred in the proband. In contrast, in family
10683, the same mutation was transmitted by the grandfather to 3 of his
grandchildren.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study, we report 3 mutations that have been found in 4 families and that cosegregated with LQTS. Two of them are new, 1032 G
C, which changes the last base of codon 344 (the last
codon of exon 6), and 922-1 GC, which affects the acceptor site of
intron 5. In addition, another variation of nucleotide
1032, 1032 GA, which was previously described in 5
families,27 28 was identified in 2 French families. Both
symptomatic and asymptomatic individuals
carrying a mutation showed a prolongation of the QT interval, with QTc
values >440 ms. Among the 14 mutation carriers, half of them were
symptomatic, and one sudden death occurred at the age of
18. Five adults remained asymptomatic, as did 2 children
who were treated by ß-blockers.
About 15% of all point mutations are believed to result in abnormal
splicing of pre-mRNA.29 The 3 mutations described here
were thought to be splicing mutations because they involve the
characteristic consensus sequences of donor and acceptor sites, which
are G/GTRAGY and YNYAG/,
respectively.30 The 2 guanines involved are shown in bold
in the above sequences. The donor site base changes that we found in 3
families concern the last base of exon 6 (G1032A and G1032C), and a G
at this position was reportedly present in 78% of
exons.31 Its change is responsible for several disease
states.31 32 33 34 In the Cardiff Mutation Database, although
not the most frequent splice defects (only 7%), there are 106 base
changes in the last base of an exon that produce splicing changes, and
all but 2 of these involve a G.35 Of the 104 such
substitutions, 64 are GA, 21 are GC, and 17 are GT (P.
Stenson, PhD, personal communication, 1998). In the fourth
family, 1 of the 2 invariant bases of the acceptor site (AG) at the
intron/exon junction is affected (922-1 GC), and such mutations
account for 
88% of point mutations in these
regions.29
Evaluation of the mutations described in this report using the method
of Shapiro and Senepathy30 gave scores of 68.6%, 67.5%,
and 61% for 1032 GA, 1032 GC, and 922-1 GC, respectively.
Complete abolition of normal splicing is the most common consequence of
a mutation of a G of the consensus splice donor or acceptor
sites.30 To determine whether this occurs with these
mutations and what the aberrant pattern of splicing might be, we
examined lymphocyte RNA using RT-PCR. Transcripts were produced from
all 3 mutations lacking exons 6 and 7. In addition, a transcript
lacking exon 7 was found in normal cardiac tissue at a low level, and
in lymphocytes from a patient with the 1032 GC base change. Such a
transcript was not determined for the 1032 GA and 922-1 GC
mutations, but this may be due to the fact that the cDNA from the
latter was from lymphoblastoid cell lines. For these 2 abnormal
transcripts, the reading frame remained intact, resulting in the
deletion of part of the pore or S6 domain, which are the major
functional regions of all potassium channels.36 In
addition, this region in KCNQ1 is involved in the
interaction with minK.37 Therefore, these various mutants
could not form functional potassium channels. Of course, the changes
seen in lymphocytes or lymphoblastoid cell lines may not reflect
exactly what occurs in cardiac tissues but, as discussed above, similar
mutations are implicated in numerous studies.31 32 33 34 A
small proportion of transcripts lacking exon 7 was observed in
lymphocytes and cardiac tissue from controls. A minor in-frame deleted
transcript has also been reported in normal brain cDNA for
KCNQ4.38 Interestingly, the 3 mutations in
KCNQ1 induce the loss of exons 6 and 7 on the mutated
allele (with no equivalent transcript in normal cDNA) and, in
addition, at least for 1032 GC, induce a higher proportion of normal
alleles lacking exon 7.
The most frequent mutations described to date in KCNQ1 are
those occurring at codon 341. These are a transition (1022 C-T), A341V,
and a transversion (1022 C-A), A341E, numbered according to the
isoform-1 sequence.39 In 65 families with a
KCNQ1 mutation, alanine at position 341 was mutated 16
times.7 21 25 40 41 42 The mutation A341V is
consistent with the accidental deamination of
5-methylcytosine in a CpG dinucleotide. In higher
vertebrates, the majority of the cytosines are 5-methylated,
and spontaneous deamination leads to a transition to thymine that
is not excised by the DNA repair system, thus leading to an
irreversible point mutation and the replacement of a CG by either TG or
CA. Analysis of the factor IX gene has shown such transitions
to be elevated 26-fold.43 Mutation 1032 GA in codon 344
is also consistent with deamination of 5-methyl
cytosine on the noncoding strand of the gene. Two other
mutations of the same nucleotide, 1032 GC (reported
here) and 1032 GT (Le Marec, MD, PhD, personal communication,
1999) are also silent transversions inducing abnormal splicing.
In human factor IX mutations, transversions at CpG
dinucleotides are elevated by 7-fold relative to other
transversions, reinforcing the fact that methylated CpG
dinucleotides are mutation hotspots.43
The CpG dinucleotide of codon 344 has the characteristics
of a mutation hotspot: independent occurrence of the typical
transition, 2 transversions at the same locus, and a high frequency of
these mutations (10 of 66 families with known KCNQ1
mutations, including 1 case that was erroneously reported as a
polymorphism44 ). The discovery of a de novo 1032 GA
mutation in 1 of the French families reported here serves to underline
the mutability of this codon. Many previous studies on mutations in
KCNQ1 did not cover the entire gene, because full primer
sets were not available. It is, therefore, probable that the proportion
of mutations accounted for by changes at position 1032 will be less
than at present when the C-terminal region is better explored.
Nonetheless, these results indicate that codon 344 is the second most
frequently mutated after codon 341, suggesting at least 2 hotspots for
mutations in KCNQ1.
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Acknowledgments |
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A. Murray was funded by the Conor Power Foundation, and P. Syrris by the British Heart Foundation. The work was supported by the Institut National de la Santé et de la Recherche Médicale (PROGRES N° 4P009D), the Association Française contre les Myopathies, and a BIOMED grant (BMH4-CT96-0028). We would like to thank Dr Igor Splawski for helpful advice and discussion.
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Footnotes |
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C. Donger and C. Fenske contributed equally to this work.
Received February 12, 1999; revision received June 7, 1999; accepted June 15, 1999.
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