(Circulation. 1999;99:1344-1347.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Homozygous Deletion in KVLQT1 Associated With Jervell and Lange-Nielsen Syndrome
From the Departmentx of Pediatrics (Cardiology) (Q.C., D.Z., Q.W., J.A.T.) and Molecular and Human Genetics (J.A.T.), Baylor College of Medicine, Texas Children's Hospital, Houston, Tex; Children's Hospital at Buffalo, Buffalo, NY (R.L.G.); Department of Medicine (A.J.M., E.K., J.L.R.,) and Department of Community and Preventive Medicine (J.L.R.), University of Rochester Medical Center, Rochester, NY; Department of Cardiology, University of Pavia, and Policlinico S. Matteo, IFCCS, Pavia, Italy (C.N., S.G.P., P.J.S.); and Hospital of the University of Munster, Munster, Germany (E.S.-B.).
Correspondence to Jeffrey A. Towbin, MD, Department of Pediatrics (Cardiology), Baylor College of Medicine, One Baylor Plaza, Room 333E, Houston, TX 77030. E-mail jtowbin{at}bcm.tmc.edu
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Abstract |
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Background—Long-QT (LQT) syndrome is a cardiac disorder that causes syncope, seizures, and sudden death from ventricular arrhythmias, specifically torsade de pointes. Both autosomal dominant LQT (Romano-Ward syndrome) and autosomal recessive LQT (Jervell and Lange-Nielsen syndrome, JLNS) have been reported. Heterozygous mutations in 3 potassium channel genes, KVLQT1, KCNE1 (minK), and HERG, and the cardiac sodium channel gene SCN5A cause autosomal dominant LQT. Autosomal recessive LQT, which is associated with deafness, has been found to occur with homozygous mutations in KVLQT1 and KCNE1 in JLNS families in which QTc prolongation was inherited as a dominant trait.
Methods and Results—An Amish family with clinical evidence of JLNS was analyzed for mutations by use of single-strand conformation polymorphism and DNA sequencing analyses for mutations in all known LQT genes. A novel homozygous 2-bp deletion in the S2 transmembrane segment of KVLQT1 was identified in affected members of this Amish family in which both QTc prolongation and deafness were inherited as recessive traits. This deletion represents a new JLNS-associated mutation in KVLQT1 and has deleterious effects on the KVLQT1 potassium channel, causing a frameshift and the truncation of the KVLQT1 protein. In contrast to previous reports in which LQT was inherited as a clear dominant trait, 2 parents in the JLNS family described here have normal QTc intervals (0.43 and 0.44 seconds, respectively).
Conclusions—A novel homozygous KVLQT1 mutation causes JLNS in an Amish family with deafness that is inherited as an autosomal recessive trait.
Key Words: long-QT syndrome • deafness • Jervell and Lange-Nielsen syndrome • potassium channel
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Introduction |
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The inherited long-QT syndrome (LQT) is characterized by prolonged QT interval on ECGs, syncope (sudden loss of consciousness), seizures, and sudden death from ventricular arrhythmias, specifically torsade de pointes.1 2 Both autosomal dominant (Romano-Ward syndrome, RWS)3 4 and autosomal recessive (Jervell and Lange-Nielsen syndrome, JLNS)5 forms of LQT have been reported. Four genes for RWS have been mapped to chromosomes 11p15.5 (LQT1),6 7 8 7q35–36 (LQT2),9 3p21–24 (LQT3),9 and 4q25–27 (LQT4),10 and 3 LQT genes (LQT1, LQT2, and LQT3) were subsequently identified,11 12 13 including the potassium channel genes KVLQT1 (LQT1)11 and HERG (LQT2)12 and the cardiac sodium channel gene SCN5A (LQT3).13 Recently, mutations in KCNE1 (minK)14 were also found to cause RWS.
JLNS is rare and is associated with congenital sensorineural deafness. It was first described in 1957 by Jervell and Lange-Nielsen5 in a Norwegian family in which 4 of the 6 children were affected by both LQT and congenital sensorineural deafness but the parents appeared normal. Three of the affected children died suddenly at the ages of 9, 5, and 4 years. Since then, several other cases of autosomal recessive LQT have been reported.15 16 17 In some cases, the heterozygous parents had moderate QTc prolongation despite the fact that the syndrome was inherited as a recessive trait. In 1997, Neyroud et al18 and Splawski et al19 reported the identification of homozygous mutations of KVLQT1 in JLNS. In both studies, LQT appeared to be inherited in an autosomal dominant fashion (ie, at least 1 of the parents was affected by LQT), and deafness was inherited in an autosomal recessive fashion. Recently, mutations in KCNE1 (minK) also have been found to cause JLNS, establishing minK as a new gene for JLNS.20
In this article, we describe a homozygous deletion of 2 bp within the second transmembrane domain of KVLQT1 (S2) in a family with 2 individuals affected with LQT and deafness. This deletion causes a frameshift and premature termination and leads to a nonfunctional KVLQT1 potassium channel.
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Methods |
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JLNS Patient Evaluation
The JLNS family described here was identified in an Amish community and referred for molecular genetic studies. Only the nuclear family allowed evaluation. Consanguinity was denied by the parents. Informed consent was obtained from all participants or their guardians in accordance with standards established by local institutional review boards. Phenotypic characterization was performed as described previously,2 with the Bazett QT correction for heart rate (ie, QTc).21
Single-Strand Conformation Polymorphism and DNA Sequence
Analysis
Genomic DNA was prepared from peripheral blood
lymphocytes or lymphoblastoid cell lines derived from Epstein-Barr
virus–transformed lymphocytes from the JLNS family and from 120
control individuals.22 Polymerase chain reaction (PCR) for
single-strand conformation polymorphism (SSCP) analysis was
performed as previously described.11
Normal and abnormal SSCP conformers were cut directly from dried gels,
eluted in 100 µL of distilled water at 55°C, and reamplified. PCR
products were fractionated in 1.5% FMC NuSieve
low-melting-temperature agarose gel and purified. Purified PCR
products (200 fmol) were sequenced directly by cycle sequencing
with the CyclistTM Exo-Pfu DNA Sequencing Kit (Stratagene). For each
sequencing reaction, 20 µCi of 
-35S-dATP and
2.5 U of the Exo-Pfu enzyme were used. PCRs were carried out in a
Perkin-Elmer System-9600 thermocycler with the following profiles: 1
cycle at 95°C for 5 minutes, 45 cycles of 95°C for 30 seconds,
55°C for 30 seconds, and 72°C for 1 minute.
Restriction Fragment Length Polymorphism Analysis
Genomic DNA was PCR amplified to yield a 200-bp fragment. One of
the primers was end labeled with [
-32P]ATP
with T4 polynucleotide kinase (NEB)
under standard conditions and included in a 20-µL PCR reaction as
described for SSCP. At the end of the PCR reaction, 10 µL of the
reaction mixture was digested in a 50-µL reaction under standard
conditions with either BglI (which is unique to the
wild-type PCR fragment) or MspI (which is unique to the
mutant PCR). After incubation at 37°C for 1.5 hours, 25 µL of
formamide buffer was added. The mixture was heated at 95°C for 3 to 5
minutes and cooled immediately on ice, and 3 µL was loaded onto 6%
urea-denaturing polyacrylamide gels
(acrylamide:bisacrylamide=19:1). The gels were
run in 1x tris borate EDTA buffer at 65 W, dried on filter
paper (Schleicher and Schuell), and exposed to x-ray film (Kodak).
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Results |
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Phenotypic Characterization
Phenotypic analysis of this Amish family revealed deafness in both children but normal hearing in the parents (as defined by clinical evaluation only), indicating that the deafness in this family is inherited as an autosomal recessive trait. ECG analysis of this family revealed that the deaf male and female children are both affected by LQT, having QTc intervals of 0.52 and 0.66 second, respectively (Figure 1
). No
ventricular tachycardia was documented in these
children. The father and mother, however, have borderline QTc intervals
of 0.43 and 0.44 second, respectively. No provocative
testing on the parents (ie, electrophysiology study with
pharmacological provocation, stress testing) was performed, however.
Therefore, with respect to the clinical expression of QTc prolongation
in this family, there is autosomal recessive inheritance with
subclinical manifestations in the heterozygous parents. With respect to
the ECG findings, however, the trait is inherited as an incomplete
dominant. These studies are consistent with the diagnosis of
JLNS in this family as well.
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Mutational Analysis
Screening for mutations in KVLQT1 with SSCP and DNA
sequencing analysis identified an abnormal SSCP conformer in
the male patient of this Amish family (proband, Figure 2A) but not from >100 control
individuals. Sequence analysis of the abnormal SSCP conformer
revealed a 2-bp deletion in the S2 transmembrane domain of
KVLQT1 (Figure 2B). This mutation results in a
frameshift and premature termination of KVLQT1.
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Cosegregation of a Homozygous Deletion in KVLQT1
With JLNS
To determine whether the 2-bp deletion was homozygous in the
affected individuals, the DNA segment that was amplified from genomic
DNA of each affected person was sequenced. The sequencing patterns,
including the deletion of the 2 nucleotides AA from both
affected individuals, were identical to that of the SSCP abnormal band
(data not shown), indicating that both affected individuals are
homozygous for the 2-bp deletion. The sequencing patterns of both
parents are identical to that of the SSCP abnormal band flanking the
2-bp deletion but are a mixture of 2 overlapping sequencing panels
within the 2-bp deletion region (data not shown). These data suggest
that the parents are heterozygous for the 2-bp deletion and that
homozygous deletion of the 2 bp in KVLQT1 cosegregates
with JLNS.
To further confirm that the affected individuals are homozygous and
that the parents are heterozygous for the 2-bp deletion, restriction
fragment length polymorphism analysis was performed. In the
analysis, genomic DNA of all family members was used to produce
the end-labeled DNA fragments by PCR (see Methods). The DNA fragments
were then digested with an allele-specific restriction digestion
enzyme, BglI or MspI. BglI cuts only
the wild-type allele, whereas MspI cuts only the mutant
allele. As shown in Figure 2C
, DNA fragments from both
affected individuals were completely cut by MspI but
remained intact after exposure to BglI, confirming that
affected individuals in the family are homozygous for the 2-bp
deletion. In contrast, DNA fragments from both parents are partially
cut by either BglI or MspI, further suggesting
that they are heterozygous for the 2-bp deletion.
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Discussion |
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In this study, we identified a new homozygous deletion in KVLQT1 cosegregating with the patients of an Amish family affected by both LQT and deafness. The deletion is located in the S2 transmembrane domain of KVLQT1, resulting in a frameshift of the predicted amino acid sequence and premature stop of KVLQT1. Because the mutation leads to a frameshift of KVLQT1 starting from the middle of domain S2, it is expected to produce a nonfunctional potassium channel because most transmembrane domains and the pore region of KVLQT1 are deleted. The 2-bp deletion may also result in instability of the mutant RNA or lead to a truncated (ie, shortened) protein that is unable to be incorporated into the membrane to form a functional channel. Together with the recent identification of 2 other KVLQT1 mutations in patients with JLNS,18 19 these data further confirm that homozygous mutations in KVLQT1 result in JLNS.
The S2 transmembrane domain of KVLQT1 has been reported to contain mutations by previous authors. Splawski et al19 identified a homozygous insertion mutation in S2 that caused a frameshift, disrupting the coding sequence of KVLQT1 after S2 and leading to a premature stop codon and a truncated protein lacking the pore region in a family with JLNS. Others, such as Chouabe et al23 and Tanaka et al,24 reported missense mutations in S2, with the clinical phenotype resulting in a variable phenotype, ranging from mild to moderate to severe RWS. In addition, Donger et al25 identified S2 mutations with widely varying clinical findings in 3 families with RWS, including several gene carriers with borderline QTc. Hence, the clinical phenotype seen with mutations in the S2 transmembrane domain is heterogeneous but, in most cases, appears to be mild.26 Chouabe et al23 performed biophysical analysis of a variety of KVLQT1 mutants, including mutations in S2, and found that no matter where the mutation occurred, the general rule is that the only discernable effect is a reduction in current density, corresponding to a dominant-negative suppression of KVLQT1 function. JLNS mutations studied also produced a dominant-negative effect, but the extent of the inhibition was lower than in RWS patients. Hence, JLNS mutations produce no functional channels and have little effect on expression of wild-type subunits with the relatively normal findings in heterozygotes. Therefore, depending on the severity of the dominant-negative effect of the different mutations, the disease is either dominant or recessive. In the latter case, the reduction in the current normally carried by the KVLQT1 subunit is so high that the defect becomes apparent in other tissues expressing this protein, the inner ear being most evident.
Tyson et al26 identified a family with normal hearing and normal QTc in the parents (400 and 430 ms) of a child with JLNS, whereas in 2 other families, the same mutation caused QT prolongation (470 ms) in 1 parent. It is likely that modification of the clinical phenotype occurs because of other genetic influences (ie, modifier genes) and environmental influences and that, in some cases, QTc depends on these influences. As noted previously by Vincent et al,27 QTc values in KVLQT1 mutation carriers may range from normal (420 to 440 ms) to severely abnormal, and this may vary even within families.
In contrast to the previous reports by Neyroud et al18 and Splawski et al19 in which at least 1 parent had clearly prolonged QTc (0.484 and 0.480 second, respectively), both parents in this study have normal or borderline QTc intervals of 0.430 to 0.440 second. Thus, the clinical expression of LQT in this family is inherited as an autosomal recessive trait with subclinical manifestations in heterozygotes (ie, the parents), which is closely related to the original descriptions of JLNS by Jervell and Lange-Nielsen,5 Levine and Woodworth,15 and Fraser et al.16 17 With respect to the ECG findings, however, the trait is inherited as an incomplete dominant trait, whereas deafness appears to be inherited as an autosomal recessive trait. This finding further extends our understanding of the clinical, genetic, and molecular genetic aspects of LQT.
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Acknowledgments |
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This work was supported by a Scientist Development Award from the American Heart Association (Dr Wang); the Caroline Weiss Law Grant for Research in Molecular Medicine (Dr Wang); the Abercrombie Cardiology Fund of Texas Children's Hospital (Dr Wang); Deutsche Forschungsgemeinshaft (Dr Schulze-Bahr); Funds of the European Union, Biomed Z Program (Dr Priori, Schwartz, and Schulze-Bahr); the Texas Children's Hospital Foundation Endowment for Pediatric Cardiac Research (Dr Towbin); and NIH grants R01 HL-33843 and R01 HL-51618 (Drs Moss, Towbin, and Schwartz). We acknowledge the secretarial and administrative support of Valerie R. Price and Amy A. Gentry.
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Footnotes |
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Guest Editor for this article was Harry Dietz, MD, Johns Hopkins University, Baltimore, Md.
Received February 5, 1998; revision received October 30, 1998; accepted December 7, 1998.
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