Pathophysiological mechanisms of dominant and recessive KVLQT1 K+ channel mutations found in inherited cardiac arrhythmias
Pathophysiological mechanisms of dominant and recessive KVLQT1 K + channel mutations found in inherited cardiac arrhythmiasBernd Wollnik1, Björn C. Schroeder1, Christian Kubisch1, Hans D. Esperer2, Peter Wieacker3 and Thomas J. Jentsch1,*
1Centre for Molecular Neurobiology (ZMNH), Hamburg University, Martinistrasse 85, D-20246 Hamburg, Germany, 2Division of Cardiology and 3Institute for Human Genetics, Magdeburg University, Leipziger Strasse 44, D-39120 Magdeburg, Germany
Received June 13, 1997;Revised and Accepted July 28, 1997
The inherited long QT syndrome (LQTS), characterized by a prolonged QT interval in the electrocardiogram and cardiac arrhythmia, is caused by mutations in at least four different genes, three of which have been identified and encode cardiac ion channels. The most common form of LQTS is due to mutations in the potassium channel gene KVLQT1, but their effects on associated currents are still unknown. Different mutations in KVLQT1 cause the dominant Romano-Ward (RW) syndromeand the recessive Jervell and Lange-Nielsen (JLN) syndrome, which, in addition to cardiac abnormalities, includes congenital deafness. Co-expression of KvLQT1 with the IsK protein elicits slowly activating potassium currents resembling the cardiac Iks current. We now show that IsK not only changes the kinetics of KvLQT1 currents, but also its ion selectivity. Several mutations found in RW, including a novel mutation (D222N) in the putative channel pore, abolish channel activity and reduce the activity of wild-type KvLQT1 by a dominant-negative mechanism. By contrast, a JLN mutationtruncating the carboxy-terminus of the KvLQT1 channel protein abolishes channel function without having a dominant-negative effect. This fully explains the different patterns of inheritance. Further, we identified a novel splice variant of the KVLQT1 gene, but could not achieve functional expression of this nor of a previously described heart-specific isoform.
The hereditary long QT syndrome (LQTS) is a congenital heart disease with frequent familial transmission. Two forms can be distinguished: (i) an autosomal dominantly inherited QT prolongation referred to as Romano-Ward (RW) syndrome (1 ); and (ii) the autosomal recessive Jervell and Lange-Nielsen (JLN) syndrome (2 ) with QT prolongation and associated congenital deafness. Characteristic changes in the electrocardiogram (ECG) are a prolongation of the heart rate-corrected QT interval (QTc) and T wave alterations, which are caused by an abnormal ventricular repolarization. Occasional syncopes are due to malignant tachyarrhythmia, usually torsade de pointes. Sudden death may occur by transformation of these ventricular arrhythmias into ventricular fibrillation. Mutations in three genes are known to cause autosomal dominant LQT syndrome, KVLQT1 (LQT1, 11p15.5) (3 -5 ), HERG (LQT2, 7q35-37) (6 ) and SCN5A (LQT3, 3p21-24) (7 ). All of them encode cardiac ion channels that are involved in the generation of the cardiac action potential. A gene for the fourth locus (LQT4, 4q25-27) has not yet been identified (8 ). Recently, it was shown that the KVLQT1 gene is also mutated in families with JLN syndrome (9 ).
The SCN5A is the pore-forming subunit of a voltage-dependent cardiac sodium channel which causes the depolarization in the ventricular action potential. LQT-associated mutations in this gene cause a defect in channel inactivation, leading to infrequent late re-openings of the channel (10 ). These late depolarizing currents prolong the action potential. This becomes apparent in an increased QT interval, and is associated with a risk of after-depolarization and arrhythmia. The product of the HERG gene is the rapidly activating cardiac delayed rectifier potassium channel Ikr (11 ). Co-expressing wild-type and mutant HERG subunits showed that most of the LQT-associated HERG mutations had a dominant-negative effect on channel function (12 ). Dysfunction of the HERG channels leads to an abnormal repolarization, causing again a susceptibility to early after-depolarization and arrhythmia.
Using PCR techniques on human heart cDNA, we searched for 5' coding sequences complementing the published partial KvLQT1 cDNA sequence (3 ) which begins within the first putative transmembrane span S1. In addition to several different isoforms found also by other groups (14 ,16 ,17 ), we identified a novel splice variant (isoform 5) which predicts an open reading frame (ORF) (Fig. 1 ). However, the first putative transmembrane span as present in the functional isoforms 0 and 1 is changed and less hydrophobic, and this isoform did not yield novel currents when expressed in Xenopus oocytes (data not shown). We also could not achieve functional expression of isoform 2. Surprisingly, it is the most abundant splice variant in heart (17 ). By contrast, and as described previously (14 ), isoform 0 induced novel currents in Xenopus oocytes which were dramatically altered (13 ,14 ) by co-expressing the IsK protein (18 ). Currents were significantly increased, and the activation by depolarization was slowed and shifted to positive voltages (Fig. 3 a). This resembles the Iks current found in ventricular myocytes. Co-expressing KvLQT1 with IsK changed the ion selectivity of currents (Table 1 ). There was a conspicuous alteration in K>Cs permeability, while PK/PRb and PK/PNa were only slightly changed. Ion selectivity is a typical pore property, suggesting that IsK modifies the KvLQT1 pore.
We identified a novel KVLQT1 mutation in a large German pedigree with autosomal dominant LQT syndrome (Fig. 2 a and b). Using single-stranded conformation polymorphism (SSCP) and direct sequencing, we identified a G -> A transition at position 664 of the coding region in exon 6, which was found in all affected members of the pedigree. (Fig. 2 b). It was not found in unaffected family members, nor on 60 control chromosomes. The mutation results in an amino acid exchange (D222N) which neutralizes a negative charge adjacent to the highly conserved GYG signature motif in the H5 pore loop of potassium channels (Fig. 2 c). While aspartate at this position is highly conserved within shaker-related potassium channels, it is-as in the mutant-replaced by an asparagine in the Drosophila eag channel and the related mammalian HERG channel (19 ). This makes the effect of the mutation difficult to predict.
We introduced this and three other KVLQT1 pore mutations (3 ,4 ) found in RW pedigrees (G211R, T217I and G219S) into isoform 0 and studied their functional effects in the Xenopus oocyte expression system. Even though an endogenous Xenopus oocyte KvLQT1 channel (14 ) may complicate the interpretation of data at low expression levels, we chose this expression system because it allows for a reasonable control of expression levels in co-injection experiments. We could not detect novel currents with any of these pore mutants, irrespective of whether they were expressed together with or without IsK (data not shown). With loss-of-function mutations, a dominant inheritance of the phenotype may be explained by haploinsufficiency or a dominant-negative effect of mutant proteins on their normal counterparts. Since shaker-type potassium channels function as tetramers, we suspected that the latter possibility holds true. We co-injected the RW mutant KvLQT1 cRNAs at a 1:1 ratio with WT KvLQT1 cRNA, and compared the current with those from oocytes injected with the same total cRNA mass of WT KvLQT1 (i.e. twice the amount of WT KvLQT1 cRNA compared with the co-injection). This largely avoids problems with saturation of translation in this non-linear expression system (20 ,21 ). If mutant channel subunits (which do not yield currents by themselves) would not interact with WT subunits, one would expect ~50% of WT current upon a 1:1 co-expression. However, current amplitudes were dramatically reduced to ~20% of WT for all RW mutants tested, indicating a dominant-negative effect. This effect did not depend on the co-expression of IsK (compare Fig. 3 b and c). Co-expressing the RW pore mutants did not change the ion selectivity (Table 1 ), compatible with an insignificant contribution of heteromeric WT/mutant channels to macroscopic currents.
We next investigated a mutant found in recessive JLN disease (9 ). It leads to a frameshift after the last transmembrane span and to a truncation of the cytoplasmic carboxy-terminus (see Fig. 2 c). Again, this mutant did not yield novel currents in the Xenopus system, either with or without co-expression of IsK (data not shown), indicating that the carboxy-terminus has some important, as yet unknown role for channel function. Co-expression with WT KvLQT1 at a 1:1 ratio yielded currents which were slightly larger than 50% of WT currents expressed from the same total amount of RNA (Fig. 3 a, d and e), fully consistent with the recessive mode of inheritance. This was observed both with (Fig. 3 d) or without (Fig. 3 e) co-expression of IsK.
It is known that the KvLQT1 gene is alternatively spliced at the 5' portion of the gene (16 ,17 ). We identified a new splice variant (isoform 5) which predicts an ORF. When expressed in Xenopus oocytes, neither this novel isoform 5, nor the previously described isoform 2, which is thought to be heart specific (17 ), yielded novel currents. This result did not depend on co-expression with WT KvLQT1 and IsK. In isoforms 2 and 5, the first putative transmembrane span is changed and less hydrophobic, and isoform 2 lacks a cytosolic N-terminus which typically precedes the first transmembrane span S1 in voltage-gated potassium channels. Thus, it is not surprising that these isoforms are non-functional, but their physiological role (if any) remains enigmatic.
While the effect of IsK on the kinetics of KvLQT1 currents (induced by isoform 0) was described before (13 ,14 ), we detected for the first time a change in ion selectivity upon co-expression of IsK (Table 1 ). This indicates that this small, single-span transmembrane protein modifies KvLQT1 pore properties. This is in contrast to the exclusive effect on kinetics of [beta]-subunits of shaker-type potassium channels. Experiments performed prior to the identification of KvLQT1 already suggested that IsK somehow participates in a K+ channel pore. When IsK is expressed singly in Xenopus oocytes, currents probably result from a combination of the exogenous IsK protein with endogenous Xenopus oocyte KvLQT1 channels (14 ). When IsK mutants were expressed (without exogenous KvLQT1) in Xenopus oocytes, most mutations affected gating only (22 ). However, a particular IsK mutation (23 ) changed the ion selectivity of IsK-induced currents. Interestingly, this mutation (F55T) most drastically affected the Cs permeability, which-as we have shown here-is strongly affected by co-expressing KvLQT1 with IsK. Xenopus oocyte currents induced by IsK F55T had a K/Cs permeability ratio (23 ) resembling that of human KvLQT1 channels lacking IsK (Table 1 ). This raises the possibility that this IsK mutant can stimulate endogenous oocyte KvLQT1 channels without changing their permeability properties. Although another study on cysteine modification mutants of IsK suggested that some IsK residues line the pore (24 ), it should be pointed out that a more indirect effect of IsK on permeability ratios cannot be strictly excluded.
The novel D222N mutation identified here is the fifth mutation described in the putative pore region of KvLQT1. Each of these mutations have been found in only one family so far. D222 directly follows the highly conserved TXXTXGYG signature motif in the pore region of the KvLQT1 channel (Fig. 2 c). Interestingly, the human HERG channel and the Drosophila eag channel have an asparagine at exactly this position (19 ). The corresponding D -> N mutant in shaker K+ channels (D447N) showed a drastically accelerated C-type inactivation (25 ). The T217I and G219S pore mutations analyzed here affect highly conserved pore residues (TXXTXGYG), while the position of G211R is less conserved (Fig. 2 c). In shaker K+ channels, G444 (equivalent to KvLQT1 G219) may be involved in ion selectivity (26 ) and T442 (T217) in N-type inactivation (27 ). In contrast, we could not detect currents with the KvLQT1 pore mutants G219S, G211R, T217I and D222N.
Voltage-gated potassium channels are tetramers of identical or homologous pore-forming [alpha]-subunits, which often associate with additional regulatory [beta]-subunits. Incorporation of mutated [alpha]-subunits into the tetrameric complex can affect the function of the channel, resulting in dominant-negative effects. This has already been observed with HERG channel mutations leading to the LQT2 syndrome (12 ). In the present study, all pore mutations associated with the dominant RW syndrome also exerted a dominant-negative effect in the Xenopus expression system, irrespective of whether these [alpha]-subunits were co-expressed with IsK. When mutants were co-expressed with WT KvLQT1 at a 1:1 ratio, currents were reduced to ~20%. If the incorporation of a single mutant subunit into the tetramer would lead to a total loss function, one would expect a more pronounced reduction (1/16 of WT currents). However, this reasoning rests on many assumptions (such as, for example, equal translation and association efficiencies), which cannot be taken for granted. Thus, we cannot draw any conclusion on how many mutant subunits are incorporated into the tetramer, and whether some of the resulting WT/mutant heteromers still yield (possibly changed) potassium currents. Interestingly, we could not detect any effects of mutants on the qualitative properties of currents (i.e. kinetics and selectivity). This suggests that mutant/WT heteromers (which may have changed properties with pore mutations) do not contribute significantly to the overall current.
In contrast to the dominant-negative effect of the tested RW mutants, co-expression of the recessive JLN mutant with WT KvLQT1 yielded currents which were slightly larger than 50% of the WT current expressed from the same total amount of RNA, not depending on co-expression with IsK. Again, expression of the mutant alone did not show novel currents. This fully explains the recessive mode of inheritance. Since the difference from the 50% level was not statistically significant, it cannot be inferred whether the truncated channel fails to associate with WT subunits, or whether it yields (partially) active channels when incorporated into the tetrameric channel at certain WT/mutant stoichiometries. Both mechanisms seem feasible with a carboxy-terminal deletion. As with the dominant RW mutants, we only observed quantitative, but not qualitative changes in currents when co-expressing this mutant.
In summary, KvLQT1 pore mutations cause the dominant (Romano-Ward) form of LQTS by partially inactivating the subunits encoded by the normal alleles in heterozygous patients. Apparently, the reduction in total current (down to ~20% if the oocyte system is representative of the in vivo situation) is sufficient to delay the repolarization of cardiac action potentials significantly, causing the prolonged QT intervals in ECGs. By contrast, this level of channel activity seems to be still compatible with normal ear function, where KvLQT1 may be important for endolymph homeostasis in the cochlea (9 ). To cause the hearing defects associated with JLN syndrome, KvLQT1 currents will have to be reduced further as in those patients who are homozygous for the functional null mutation investigated here. This also explains the more severe cardiac phenotype of JLN patients. The inner ear defects characteristic of JLN would probably also be observed if RW mutations were present in a homozygous state. The main difference between RW and JLN mutations in KVLQT1 is the presence or absence, respectively, of a dominant-negative effect on the gene product of the WT allele.
The family with RW syndrome was clinically investigated in the Division of Cardiology, Universities of Hannover and Magdeburg. Phenotyping was performed on the basis of clinical history and QT interval in electrocardiograms corrected for heart rate (QTc) using Bazett's formula (28 ). All individuals classified as affected showed a prolonged QTc on ECG. In contrast to the other affected family members, individual IV-12 was clinically asymptomatic, although QTc values were markedly increased (to 560 ms). Informed consent was obtained from the subjects and blood samples were taken for the preparation of genomic DNA. Exons 2-7 of the KVLQT1 gene of index patient III 10 (Fig. 2 a) were amplified by PCR using intronic primers (3 ). SSCP analysis [using 15% non-denaturing gels (CleanGels, ETC) and a Multiphor II electrophoresis system (Pharmacia)] suggested a mutation in exon 6 which was analyzed by direct sequencing of the PCR product using anABI 377 system (Applied Biosystems). This revealed the D222N mutation which was found in a heterozygous state (Fig. 2 b).
KvLQT1 and IsK cDNAs were cloned using a Human Heart Marathon-Readytm cDNA Kit (Clontech) by PCR techniques using primers against the published sequences and the Expandtm Long Template PCR System (Boehringer Mannheim). This kit was also used to amplify different 5' splice forms of the KVLQT1 gene. PCR products were directly sequenced, and final constructs were cloned into the expression vector pTLN which contains Xenopus [beta]-globin untranslated sequence to boost expression (29 ). The KvLQT1 initiator ATG was always cloned into the NcoI site which provides an optimal Kozak consensus sequence for eukaryotic initiation. In the case of isoform 5, this resulted in a change of the second amino acid from leucine to valine. KVLQT1 mutations were inserted into isoform 0 in pTLN using recombinant PCR and Pfu polymerase (Stratagene). Constructs used for expression studies were fully sequenced on both strands using an ABI 377 system (Applied Biosystems).
Constructs in pTLN (29 ) were linearized with MluI, which cuts after the 3' [beta]-globin untranslated region, and capped cRNA was transcribed in vitro by SP6 RNA polymerase using the mMessage mMachine cRNA synthesis kit (Ambion). cRNA was injected into Xenopus oocytes which were dissected manually from the ovary. Oocytes were kept in modified Barth's solution at 17oC [88 mM NaCl, 2.4 mM NaHCO3, 1 mM KCl, 0.41 mM CaCl2, 0.33 mM CaNO3, 0.82 mM MgSO4, 10 mM HEPES, 100 U Penicillin-100 [mu]g streptomycin/ml (Gibco), pH 7.6]. They were analyzed at room temperature in ND96 saline (96 mM NaCl, 2 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 5 mM HEPES, pH 7.4) after 2 days by two-electrode voltage-clamping using a Turbotec amplifier (Npi Instruments) and pCLAMP 5.5 software (Axon Instruments). Solutions for ion selectivity measurements were composed of 100 mM XCl (X = Na, Cs, Rb or K), 2.8 mM MgCl2, 1 mM CaCl2, 5 mM HEPES, pH 7.4, titrated with NaOH.
We thank the family members for their cooperation and C. Neff for technical assistance. This work was supported by grants from the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie to T.J.J.
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